The general tone of the novel is one of extreme disillusionment with Depression-era American society, a consistent theme throughout West's novels. However, the novel is a black comedy, characterized by a dark sense of humor and irony. Justus Neiland, among others, has pointed out the use of Bergsonian laughter, in which “the attitudes, gestures, and movements of the human body are laughable in exact proportion as that body reminds us of a machine.” 
The novel can be read as a condemnation of alienation and the colonization of social life by commodification, foreshadowing the stance of the Situationists and Guy Debord in particular. Miss Lonelyhearts is unable to fulfill his role as advice giver in a world in which both people and advice (in the form of newspaper ads, for example) are mass-produced. People are machines for the sole purpose of laboring as far as the rest of society is concerned (thus Miss Lonelyhearts' name), and any advice for them is as mass-produced as a manual for a machine. Lonelyhearts is unable to find a personal solution to his problems because they have systemic causes. West, who worked in the newspaper business before writing Miss Lonelyhearts, is also an advice giver of a sort as a novelist. Miss Lonelyhearts is similar to a détournement because it uses a form to critique the same form. The novel also condemns itself by condemning art, which is repeatedly derided by Shrike and compared to religion as an opiate of the masses.
Many of the problems described in Miss Lonelyhearts describe actual economic conditions in New York City during the Great Depression, although the novel carefully avoids questions of national politics. Moreover, the novel is particularly important due to its existential import. The characters seem to be living in an amoral world. Hence, they resort to heavy drinking, sex, and parties. Miss Lonelyhearts has a "Christ complex", which stands for his belief in religion as a solution to a world devoid of values.