Clark began his journalistic career with the New York Mirror, then the Columbian Star, and the Philadelphia Gazette. It was in Philadelphia that he met Anne Poyntell Caldcleugh, whom he married in 1836. Soon, however, she was sick with tuberculosis and died shortly after marriage. Clark was deeply affected — especially when he began showing symptoms of the disease as well. His poetry became distinctly morbid, including his poem "The Dying Poet." Its second-to-last stanza reads:
Farewell to life! its morning hour
Was like a golden paradise;
Hope sprang like some luxuriant flower,
Where youth's enchanted visions rise!
I have had peace — its hour was brief:
I have had care — it lingered long!
Joy's tree sent down its faded leaf,
On Pleasure's lip expired the song!
After the death of Willis, Lewis stepped up his presence in the literary world, especially in New York.Years earlier, he purchased the floundering Knickerbocker magazine (first edited by Charles Fenno Hoffman). He served as its editor until 1861. Lewis also oversaw the publication of The Literary Remains of Willis Gaylord Clark (1844).