Notable images he popularized were:
- in 1863 he drew Santa Claus for Harper's Weekly
- the Republican Party Elephant
- the Democratic Party Donkey
- the Tammany Hall Tiger, a symbol of Boss Tweed's political machine that controlled New York City.
- John Bull, a rotund image of Britain's spirit
- Uncle Sam, a lanky image of the United States.
- Columbia, a graceful image of the Americas as a woman, usually in flowing gown and tiara, carrying a sword to defend the downtrodden.
- John Chinaman, a sympathetic image of chinese immigrants.
He was trained at New York City's National Academy of Design. He studied with Alfred Fredericks and Theodore Kaufmann. After school (at the age of 15), he started working in 1855 at the Illustrated Newspaper owned by Frank Leslie. He drew for Harper's Weekly from 1859 until 1886. After the death of Fletcher Harper, he focused on oil paintings and book illustrations. In the early 1860s, he married Sarah Edwards.
He was well known for his political cartoons, supporting American Indians, Chinese, and advocating abolition of slavery. His biting wit was generally focused on political corruption, and was instrumental in the downfall of Boss Tweed. It was said a political cartoon drawn by Nast was used by the officials of Spain when Tweed fled justice there. Andrew Johnson was another target of his.
He shared political views with his friend Mark Twain.
Before his work in political cartoons, he worked as a correspondent of Harper's Weekly, known for his on the scene sketches of the Civil War, drawing both Border States and Southern battlefields. In 1890, he published Thomas Nast's Christmas Drawings for the Human Race. He tried to start a magazine, which failed. Theodore Roosevelt appointed him as United States' Consul General to Guayaquil Ecuador in South America. At age 62, in 1902, he died of yellow fever contracted there.