In 1880, President Rutherford B. Hayes had nominated Stanley Matthews to the Supreme Court of the United States, but the Senate declined to act on the Matthews nomination. In March 1881, Garfield re-nominated Matthews to the Supreme Court. The Senate confirmed Matthews by a vote of 24-23.

Highly educated and intellectually curious, Lucretia Garfield was well attuned to the internal machinations of the Republican Party, which proved to be of great aid to her husband's political career. She returned to her former residence in Ohio after being widowed, living in what is now the James A. Garfield National Historic Site. She spent much of the rest of her life preserving her husband's papers and other materials, establishing what was effectively the first presidential library.

Garfield was shot by Charles J. Guiteau, a disgruntled office seeker, at the Baltimore and Potomac Railroad Station in Washington, D.C. on July 2, 1881. After eleven weeks of intensive care Garfield died in Elberon, New Jersey, on September 19, 1881. Guiteau was executed for Garfield's murder in June 1882.

Alexander Graham Bell tried to locate the bullet with a primitive metal detector. He was not successful, although the invention did manage to detect the metal in the president's mattress.

As Garfield attempted to recover from his wounds, one means of keeping him comfortable in Washington's summer heat was one of the first successful air conditioning units. Air that was propelled by fans over ice and then dried reduced the temperature in the sickroom by 20 degrees Fahrenheit. Engineers from the navy, along with some scientists, worked together to develop this version of air conditioning in an attempt to help the president recover.

$5 bills issued in 1882 featured a portrait of Garfield. They are called brown backs by collectors because the back of each note is brown. Depending on the serial number, condition, and most importantly the bank of issue, these bills today can be worth as little as $200 or as much as $10,000.