MacKinnon's ideas may be divided into three central—although overlapping and ongoing—areas of focus: (1) sexual harassment, (2) pornography, and (3) international work. She has also devoted attention to social and political theory and methodology.
According to an article published by Deborah Dinner in the March/April 2006 issue of Legal Affairs, MacKinnon first became interested in issues concerning sexual harassment when she heard that an administrative assistant at Cornell University resigned after being refused a transfer when she complained of her supervisor's harassing behavior, and then was denied unemployment benefits because she quit for "personal" reasons. It was at a consciousness-raising session about this and other women's workplace experiences, organized by Lin Farley as part of a Cornell class on women and work, that the term "sexual harassment" was coined.
In 1977, MacKinnon graduated from Yale Law School after having written a paper on sexual harassment for Professor Thomas I. Emerson. Two years later, MacKinnon published "Sexual Harassment of Working Women", arguing that sexual harassment is a form of sex discrimination under Title VII of the Civil Rights Act of 1964 and any other sex discrimination prohibition. While working on "Sexual Harassment", she shared draft copies with attorneys litigating early sexual harassment cases, including Nadine Taub, who represented Yale undergraduates in Alexander v. Yale, the first test case of MacKinnon's legal theory.
In her book, MacKinnon argued that sexual harassment is sex discrimination because the act reinforces the social inequality of women to men (see, for example, pp. 116–18, 174). She distinguishes between two types of sexual harassment (see pp. 32–42): 1) "quid pro quo", meaning sexual harassment "in which sexual compliance is exchanged, or proposed to be exchanged, for an employment opportunity (p. 32)" and 2) the type of harassment that "arises when sexual harassment is a persistent condition of work (p. 32)". In 1980, the Equal Employment Opportunity Commission followed MacKinnon's framework in adopting guidelines prohibiting sexual harassment by prohibiting both quid pro quo harassment and hostile work environment harassment (see 29 C.F.R. § 1604.11 (a)).
In 1986, the Supreme Court held in Meritor Savings Bank v. Vinson that sexual harassment may violate laws against sex discrimination. In Meritor, the Court recognized the distinction between quid pro quo sexual harassment and hostile workplace harassment. In a 2002 article, MacKinnon wrote:
"'Without question,' then-Justice Rehnquist wrote for a unanimous Court, 'when a supervisor sexually harasses a subordinate because of the subordinate's sex, that supervisor "discriminate[s]" on the basis of sex.' The D.C. Circuit, and women, had won. A new common law rule was established."
MacKinnon's book, Sexual Harassment of Working Women: A Case of Sex Discrimination, is the eighth most-cited American legal book published since 1978, according to a study published by Fred Shapiro in January 2000. 
MacKinnon, along with late feminist activist Andrea Dworkin, has been active in attempting to change legal postures towards pornography by framing it as a form of sex discrimination and, more recently, a form of human trafficking. She (and Dworkin) define pornography as follows:
"We define pornography as the graphic sexually explicit subordination of women through pictures and words that also includes (i) women are presented dehumanized as sexual objects, things, or commodities; or (ii) women are presented as sexual objects who enjoy humiliation or pain; or (iii) women are presented as sexual objects experiencing sexual pleasure in rape, incest or other sexual assault; or (iv) women are presented as sexual objects tied up, cut up or mutilated or bruised or physically hurt; or (v) women are presented in postures or positions of sexual submission, servility, or display; or (vi) women's body parts—including but not limited to vaginas, breasts, or buttocks—are exhibited such that women are reduced to those parts; or (vii) women are presented being penetrated by objects or animals; or (viii) women are presented in scenarios of degradation, humiliation, injury, torture, shown as filthy or inferior, bleeding, bruised, or hurt in a context that makes these conditions sexual."
In Toward a Feminist Theory of the State, MacKinnon writes, "Pornography, in the feminist view, is a form of forced sex, a practice of sexual politics, and institution of gender inequality." MacKinnon chooses a few points to focus on specifically, depicting the sexual exploitation of women as a means of showing their inferiority by displaying them as sexual objects, things or commodities, which dehumanizes them. She argues that any display of women enjoying humiliation or pain should be a violation of the law. She writes, "Pornography contributes causally to attitudes and behaviors of violence and discrimination which define the treatment and status of half the population."
In 1980, Linda Boreman (who had appeared, under the name Linda Lovelace in the pornographic film Deep Throat) claimed her ex-husband Chuck Traynor had violently coerced her into making Deep Throat and other pornographic films. Boreman made her charges public for the press corps at a press conference, together with MacKinnon, members of Women Against Pornography, and feminist writer Andrea Dworkin offering statements in support. After the press conference, Dworkin, MacKinnon, Boreman, and Gloria Steinem began discussing the possibility of using federal civil rights law to seek damages from Traynor and the makers of Deep Throat. Boreman was interested but backed off after Steinem discovered that the statute of limitations for a possible suit had passed (Brownmiller 337).
MacKinnon and Dworkin continued to discuss civil rights litigation as a possible approach to combating pornography. MacKinnon opposed traditional arguments against pornography based on the idea of morality or sexual innocence, as well as the use of traditional criminal obscenity law to suppress pornography. Instead of condemning pornography for violating "community standards" of sexual decency or modesty, they characterized pornography as a form of sex discrimination and sought to give women the right to seek damages under civil rights law. "Pornography, in the feminist view is a form of forced sex, a practice of sexual politics, an institution of gender inequality" (Mackinnon 197).
In 1983, the Minneapolis city government hired MacKinnon and Dworkin to draft an antipornography civil rights ordinance as an amendment to the Minneapolis city civil rights ordinance. The amendment defined pornography as a civil rights violation against women and allowed women who claimed harm from pornography to sue the producers and distributors for damages in civil court. The law was passed twice by the Minneapolis city council but vetoed by the mayor. Another version of the ordinance passed in Indianapolis, Indiana in 1984, but was ruled unconstitutional by the Seventh Circuit Court of Appeals. She continued to support the civil rights approach in her writing and activism, and supported anti-pornography feminists who organized later campaigns in Cambridge, Massachusetts (1985) and Bellingham, Washington (1988) to pass versions of the ordinance by voter initiative.
MacKinnon wrote in the Harvard Civil Rights-Civil Liberties Law Review in 1985:
And as you think about the assumption of consent that follows women into pornography, look closely some time for the skinned knees, the bruises, the welts from the whippings, the scratches, the gashes. Many of them are not simulated. One relatively soft core pornography model said, "I knew the pose was right when it hurt." It certainly seems important to the audiences that the events in the pornography be real. For this reason, pornography becomes a motive for murder, as in "snuff" films in which someone is tortured to death to make a sex film. They exist."
MacKinnon represented Boreman from 1980 until Boreman's death in 2002. Civil libertarians frequently find MacKinnon's theories objectionable (see "Criticisms" section), arguing there is no evidence that sexually explicit media encourages or promotes violence against, or other measurable harm of women. One laboratory study found that possible temporary effects of pornography may dissipate over time.
In February 1992, the Supreme Court of Canada largely accepted MacKinnon's theories of equality, hate propaganda, and pornography, citing extensively from a brief she co-authored in a ruling against Manitoba pornography distributor Donald Butler. The Butler decision was controversial; it is sometimes implied that shipments of Dworkin's book Pornography were seized by Canadian customs agents under this ruling, as well as books by Marguerite Duras and David Leavitt; the books were indeed seized by customs, but not as a consequence of Butler. Successful Butler prosecutions have been undertaken against the lesbian sadomasochistic magazine Bad Attitude, as well as the owners of a gay and lesbian bookstore for selling it. Canadian authorities raided an art gallery and confiscated controversial paintings depicting child abuse. Many free speech and gay rights activists have alleged that the law is selectively enforced, targeting the LGBT community. MacKinnon represented Bosnian and Croatian women against Serbs accused of genocide since 1992. She was co-counsel, representing named plaintiff S. Kadic, in Kadic v. Karadzic and won a jury verdict of $745 million in New York City on August 10, 2000. The lawsuit (under the United States' Alien Tort Statute) established forced prostitution and forced impregnation as legally actionable acts of genocide. In MacKinnon's view, traditional approaches to human rights gloss over abuses specific to women (e.g., sexual violence), both in wartime and peacetime. MacKinnon has worked to change laws, or their interpretation and application in Mexico, Japan, Israel, and India. In 2001, MacKinnon was named co-director of the Lawyers Alliance for Women (LAW) Project, an initiative of Equality Now, an international non-governmental organization.