Grissom was born in Mitchell, Indiana. He later went to Purdue University where he got a degree in mechanical engineering. After serving as a combat pilot in the Korean conflict, he studied aeronautical engineering at the Air Force Institute of Technology. Grissom then attended the Air Force Test Pilot School at Edwards Air Force Base, California. He then became a test pilot at Wright-Patterson Air Force Base in Ohio.

In 1959, Grissom was chosen by NASA as one of the original seven Mercury astronauts. His first space flight was a 15-minute suborbital Mercury flight (July 21, 1961). His capsule, called the Liberty Bell 7, splashed down in the Atlantic Ocean as planned. The emergency exit hatch blew open as it landed. Grissom was rescued by a helicopter, but the space capsule sank.

His second space flight was the two-man Gemini 3 flight. With him aboard Gemini 3 was the astronaut John Young. This flight orbited for five hours (three revolutions around the Earth).

Grissom was later chosen to be the commander of the first Apollo mission (Apollo 1). He died on January 27, 1967, during an Apollo training session (in which they were practicing emergency procedures). A flash fire quickly burned the spacecraft, killing Grissom and his fellow astronauts Edward White II and Roger Chaffee. Grissom is buried in Arlington National Cemetery, in Arlington, Virginia.