From 1816 to 1825, Bryant depended on his law practice in Great Barrington, Massachusetts to sustain his family financially, but the strain of dealing with unsophisticated neighbors and juridical pettifoggery pushed him to trade his unrewarding profession for New York City and the promise of a literary career. With the encouragement of a distinguished and well-connected literary family, the Sedgwicks, he quickly gained a foothold in New York City's vibrant cultural life. His first employment, in 1825, was as editor of the New-York Review, which within the next year merged with the United States Review and Literary Gazette. But in the throes of the failing struggle to raise subscriptions, he accepted part-time duties with the New-York Evening Post under William Coleman; then, partly because of Coleman's ill health, traceable to the consequences of a duel and then a stroke, Bryant's responsibilities expanded rapidly. From Assistant Editor he rose to Editor-in-Chief and co-owner of the newspaper that had been founded by Alexander Hamilton. Over the next half century, the "Post" would become the most respected paper in the city and, from the election of Andrew Jackson, the major platform in the Northeast for the Democratic Party and subsequently of the Free Soil and Republican Parties. In the process, the Evening-Post also became the pillar of a substantial fortune. From his Federalist beginnings, Bryant had shifted to being one of the most liberal voices of the century. An early supporter of organized labor, with his 1836 editorials the right of workmen to strike, Bryant also defended of religious minorities and immigrants, and promoted the abolition of slavery. He “threw himself into the foreground of the battle for human rights” and did not cease speaking out against the corrupting influence of certain bankers in spite of their efforts to break down the paper. According to newspaper historian Frank Luther Mott, Bryant was ‘a great liberal seldom done justice by modern writers’.
Ironically, the boy who first tasted fame for his diatribe against Thomas Jefferson and his party became one of the key supporters in the Northeast of that same party under Jackson. Bryant's views, always progressive though not quite populist, in course led him to join the Free Soilers, and when the Free Soil Party became a core of the new Republican Party in 1856, Bryant vigorously campaigned for John Frémont. That exertion enhanced his standing in party councils, and in 1860, he was one of the prime Eastern exponents of Abraham Lincoln, whom he introduced at Cooper Union. (That "Cooper Union speech" lifted Lincoln to the nomination, and then the presidency.)
Although literary historians have neglected his fiction, Bryant's stories over the seven-year period from his time with the Review to the publication of Tales of Glauber Spa in 1832 show a variety of strategies, making him the most inventive of practitioners of the genre during this early stage of its evolution.
Bryant edited the very successful Picturesque America which was published between 1872 and 1874. This two-volume set was lavishly illustrated and described scenic places in the United States and Canada.