After receiving a pardon from the subsequent governor, Worcester left Georgia on a promise to never return. He moved to Indian Territory in 1836 in the period of Cherokee removal on the Trail of Tears. His wife died there in 1839. Worcester resumed his ministry, and continued translating the Bible into Cherokee.

Samuel Worcester, a missionary, defied Georgia through peaceful means to protest the state's handling of Cherokee lands. He was arrested several times as a result. With a team of lawyers, Worcester filed a lawsuit against the state that went all the way to the Supreme Court, where he finally won his case.

Worcester argued that Georgia had no right to extend its laws to Cherokee territory. He contended that the act under which he had been convicted violated the U.S. Constitution, which gives to the U.S. Congress the authority to regulate commerce with Native Americans.