Garrison worked as a compositor for his hometown newspaper in his teens, then began writing articles as well, often under the pseudonym Aristides. He soon became involved with the opposition to slavery, writing then becoming co-editor of the Quaker Genius of Universal Emancipation newspaper.
Garrison made a name for himself as one of the most articulate, as well as most radical, opponents of slavery. While some other abolitionists of the time favored gradual emancipation, Garrison argued for "immediate and complete emancipation of all slaves". When someone attending one of Garrison's speeches objected that slavery was protected by the United States Constitution, Garrison replied that if this was true, then the Constitution should be burnt.
His outspoken views repeatedly brought him trouble; he was imprisoned for libel when he called a slave trader a robber and murderer; the government of the State of Georgia offered a reward of $5,000 for his arrest, and he received numerous and frequent death threats.
In 1831 he founded an anti-slavery newspaper of his own, The Liberator, which he continued to publish and edit for 35 years.
In 1833, Garrison founded the American Anti-Slavery Society.
In 1833 he visited the United Kingdom and assisted in the anti-slavery movement there.
After the abolition of slavery in the United States, Garrison continued working on other reform movements, including favoring the rights of women to vote.