At the time, Chicago was becoming the gateway to the West. Railroads had just linked it to the east. Fuller built a law practice in Chicago. Within two years, he appeared before the Supreme Court of Illinois in the case of Beach v. Derby. He became a leading attorney in the city. He first appeared before the United States Supreme Court in the case of Traders' Bank v. Campbell. He also argued the case of Tappan v. the Merchants' National Bank of Chicago, which was the first case heard by Chief Justice Morrison Waite, whom he would later replace.
President Grover Cleveland nominated him for the Chief Justice position when Morrison Waite died in 1888. Fuller was not the first man to be mentioned as a possible Supreme Court nominee; the former ambassador to Great Britain, Edward J. Phelps, was perceived as the front-runner for the nomination. Fuller's nomination was tepidly received in the Senate. However, he was eventually confirmed by a vote of 41 to 20, with nine Republicans voting with the Democrats to confirm him.
On the bench, he oversaw a number of memorable or important opinions. The famous phrase "Equal Justice Under Law" apparently paraphrases his opinion in Caldwell v. Texas, 137 U.S. 692 (1891) where Fuller discussed "equal and impartial justice under the law. He also declared the income tax law unconstitutional in Pollock v. Farmers' Loan & Trust Co., 157 U.S. 429. In Western Union Telegraph Company v. The Commonwealth of Pennsylvania 128 U.S. 39 he ruled that states could not tax interstate telegraph messages. He struck a blow against government antitrust legislation with the 1895 case United States v. E. C. Knight Co.. In Fuller's majority decision, he found that the refining of sugar by a company within the boundaries of one state could not be held to be in restraint of interstate commerce under the terms of the 1890 Sherman Antitrust Act, regardless of the product's final market share. (E.C. Knight Company's owner, the American Sugar Refining Company, controlled more than 90% of sugar production at the time). He sided with the 8-man majority ruling in favor of "separate but equal" segregation in Plessy v. Ferguson. On immigration, Fuller ruled in 1904 that under the immigration laws Puerto Ricans were not aliens, and therefore could not be denied entry into the United States. Fuller, however declined to declare that Puerto Ricans were U.S. citizens. The question of the citizenship status of the inhabitants of the new island territories, their situation remained confusing, ambiguous, and contested. Puerto Ricans came to be known as something in between: "noncitizen nationals". In this famous immigration case, Isabel Gonzalez arrived from Puerto Rico at Ellis Island in August 1902. Immigration Commissioner William Williams held her as an "illegal" with plans to deport Gonzalez back to San Juan, Puerto Rico. She appealed her case, whereby Fuller ruled in favor of Gonzalez and allowed her to remain in the US. Fuller did not go so far as to claim that she was automatically a US citizen, however, he recognized that Puerto Rico was a territory of the US (as of the 1898 Spanish American War), and therefore Isabel had the right to remain in the US. This paved the way for future Puerto Ricans to freely immigrate to the US. Later, in 1917 the Jones Act was passed by Congress which provided for even more immigration/citizenship rights to Puerto Ricans.
According to one study, while on the Supreme Court, Fuller voted in favor of civil rights for African Americans in 15.15% (5 of 33) of the cases before him and voted in favor of civil rights for Asian Americans in 24.14% (7 of 29) of cases before him. Both percentages were below the average for the Supreme Court as a whole.
In 1893, he turned down an offer from President-Elect Grover Cleveland to serve as Secretary of State; it was the third time he turned down a government job offer from Cleveland.
He was said to closely resemble Mark Twain. Once, when the humorist was stopped on the street, a passerby demanded the Chief Justice's autograph. Twain supposedly wrote:
He was married twice. He married Calista Reynolds in 1858; she died in 1864. He married Mary Coolbaugh in 1866. He had six daughters.