Greeley was a printer's apprentice in East Poultney, Vermont, until moving to New York City in 1831, where he eventually became a founding editor of a new literary paper, The New-Yorker (1834). A liberal Whig (Whig Party), Greeley caught the attention of New York political boss Thurlow Weed (Weed, Thurlow) and was asked to issue political campaign weeklies during the elections of 1838 and 1840. These publications substantially aided the Whig cause and marked the beginning of Greeley's political partnership with Weed and New York Governor William H. Seward (Seward, William H) (U.S. secretary of state, 1861–69)—a partnership that lasted until 1854.

Greeley's journalistic success encouraged him to embark on a more ambitious newspaper venture. The New York Tribune, which he founded in 1841 and edited until his death, became a daily Whig paper dedicated to a medley of reforms, economic progress, and the elevation of the masses. The Tribune set a particularly high standard in its news gathering, intellectual interest, and moral fervour. Greeley, who published a prodigious trove of cogent articles and editorials, came to be considered the outstanding newspaper editor of his time; his large and competent staff (which included European correspondence from Karl Marx (Marx, Karl) and Friedrich Engels (Engels, Friedrich), who wrote under Marx's name) cooperated to make the paper a political bible for many readers throughout the North. Reflecting his highly moral New England upbringing, Greeley was an unrelenting foe of liquor, tobacco, gambling, prostitution, and capital punishment. He became, in the words of Harper's Weekly (1869), “the most perfect Yankee the country has ever produced.” Because of Greeley's eclectic interests, many causes found a voice in the pages of the Tribune. While The New York Times cultivated a sober tone of moderation, and the New York Herald was jingoistic and often pro-business and pro-South, the Tribune defied categorization, promoting a wide variety of interests and causes. Greeley urged a number of educational reforms, especially free common-school education for all; he championed producers' cooperatives but opposed woman suffrage. He also pushed for Western expansion but did not coin, as commonly claimed, the famous phrase “Go West, young man.” (See Researcher's Note.)

After the onset of the Civil War (1861), Greeley pursued an erratic course, though generally he sided with the Radical Republicans (Radical Republican) in advocating early emancipation of the slaves and, later, civil rights for freedmen (Freedmen's Bureau).

Greeley lost much public respect by opposing Lincoln's renomination in 1864 and by signing the bail bond of former Confederate president Jefferson Davis (Davis, Jefferson) in 1867.