Born in Portland, Maine, Willis came from a family of publishers. His grandfather Nathaniel Willis owned newspapers in Massachusetts and Virginia, and his father Nathaniel Willis was the founder of Youth's Companion, the first newspaper specifically for children. Willis developed an interest in literature while attending Yale College and began publishing poetry. After graduation, he worked as an overseas correspondent for the New York Mirror. He eventually moved to New York and began to build his literary reputation. Working with multiple publications, he was earning about US$100 per article and between $5,000 and $10,000 per year. In 1846, he started his own publication, the Home Journal, which was eventually renamed Town and Country. Shortly after, Willis moved to a home on the Hudson River where he lived a semi-retired life until his death in 1867.
Willis embedded his own personality into his writing and addressed his readers personally, specifically in his travel writings, so that his reputation was built in part because of his character. Critics, including his sister in her novel Ruth Hall, occasionally described him as being effeminate and Europeanized. Willis also published several poems, tales, and a play. Despite his intense popularity for a time, at his death Willis was nearly forgotten.
On June 20, 1839, Willis's play Tortesa, the Usurer premiered in Philadelphia at the Walnut Street Theatre. Edgar Allan Poe called it "by far the best play from the pen of an American author."
While Willis was editor of the Evening Mirror, its issue for January 29, 1845, included the first printing of Poe's poem "The Raven" with his name attached. In his introduction, Willis called it "unsurpassed in English poetry for subtle conception, masterly ingenuity of versification, and consistent, sustaining of imaginative lift ... It will stick to the memory of everybody who reads it." Willis and Poe were close friends, and Willis helped Poe financially during his wife Virginia's illness and while Poe was suing Thomas Dunn English for libel. Willis often tried to persuade Poe to be less destructive in his criticism and concentrate on his poetry. Even so, Willis published many pieces of what would later be referred to as "The Longfellow War", a literary battle between Poe and the supporters of Henry Wadsworth Longfellow, whom Poe called overrated and guilty of plagiarism. Willis also introduced Poe to Fanny Osgood; the two would later carry out a very public literary flirtation.
In 1850 he assisted Rufus Wilmot Griswold in preparing an anthology of the works of Poe, who had died mysteriously the year before. Griswold also wrote the first biography of Poe in which he purposely set out to ruin the dead author's reputation. Willis was one of the most vocal of Poe's defenders, writing at one point: "The indictment (for it deserves no other name) is not true. It is full of cruel misrepresentations. It deepens the shadows unto unnatural darkness, and shuts out the rays of sunshines that ought to relieve them."
In July 1860, Willis took his last major trip. Along with his wife, he stopped in Chicago and Yellow Springs, Ohio, as far west as Madison, Wisconsin, and also took a steamboat down the Mississippi River to St. Louis, Missouri, and returned through Cincinnati, Ohio and Pittsburgh, Pennsylvania. In 1851, Willis allowed the Home Journal to break its pledge to avoid taking sides in political discussions when the Confederate States of America was established, calling the move a purposeful act to bring on war. On May 28, 1861, Willis was part of a committee of literary figures—including William Cullen Bryant, Charles Anderson Dana, and Horace Greeley—to invite Edward Everett to speak in New York on behalf of maintaining the Union. The Home Journal lost many subscribers during the American Civil War, Morris died in 1864, and the Willis family had to take in boarders and for a time turned Idlewild into a girls' school for income.
Willis was very sick in these final years: he suffered from violent epileptic seizures and, early in November 1866, fainted in the streets, prompting Harriet Jacobs to return to help his wife. Willis died on his sixty-first birthday, January 20, 1867, and was buried in Mount Auburn Cemetery in Cambridge, Massachusetts. Four days later, the day of his funeral, all bookstores in the city were closed as a token of respect. His pallbearers included Longfellow, James Russell Lowell, Oliver Wendell Holmes, Samuel Gridley Howe, and James Thomas Fields.