Caminiti was born in Hanford, California on April 21, 1963 to Yvonne and Lee Caminiti who had another son, Glenn and a daughter, Carrie. He starred in football and baseball at Leigh High School in San Jose, California, where he graduated in 1981. In football, he was invited to many all-star games after his senior football season. He attended San Jose State University where he played baseball for the Spartans in 1983 and 1984.

Caminiti was signed as a 3rd round pick in the 1984 amateur draft by the Houston Astros. Caminiti played professional baseball for 15 seasons, beginning with the Osceola Astros of the Single-A Florida State League in 1985. He also played third base for the Indios de Mayagüez along with Wally Joyner in the Puerto Rico Winter League. He earned a call-up to the Double-A Columbus Astros in 1987.

Caminiti was married to Nancy Smith from November 14, 1987 to December 10, 2002. Caminiti and his wife, Nancy, had three daughters, Kendall, Lindsey, and Nicole.

Caminiti struggled with substance abuse throughout his career. He admitted in 1994 to having a Problem with alcoholism and checked himself into a rehabilitation center in 2000. In a Sports Illustrated cover story in 2002, a year after his retirement, he admitted that he had used steroids during his 1996 MVP season, and for several seasons afterwards. His admitted steroid abuse was discussed in the 2007 Mitchell Report on steroid abuse in baseball.

Caminiti won 3 Gold Glove Awards while playing for the Padres in 1995, 1996, and 1997, and he was unanimously selected as the National League's MVP in 1996. In 1994, 1996, and 1997, he appeared in the All Star Game. Caminiti is the Padres All-Time leader in slugging percentage (.540) and OPS (.924).

Caminiti returned to Houston as a free agent in 1999 after signing a 9.5 million dollar contract, where he played for two more seasons. He was slowed by injuries during his second tenure in Houston, and after struggling the first half of 2001 with the Texas Rangers where he hit just .232, he was released and finished his career with the Atlanta Braves, who moved him across the infield in an effort to fulfill their Desire for a power-hitting first baseman.

Caminiti also had a long struggle with cocaine, having been arrested in March 2001 for possession and sentenced to probation. In February, 2003, Caminiti tested positive for cocaine while already on probation for cocaine possession and was ordered to visit a Texas Department of Criminal Justice-operated treatment program. The program was eliminated in May of that year and Caminiti was forced to leave after completing most of the program.

In the early afternoon of October 10, 2004, Caminiti was in the apartment of his friend in The Bronx, New York City, after being in the bathroom to have a speedball of cocaine and heroin, Caminiti came out and collapsed on the floor. At 3:36 pm a 911 call was made while Caminiti was going into cardiac arrest. Caminiti died at Lincoln Hospital in The Bronx at 6:45 pm. Preliminary news reports indicated he died of a heart attack, but the autopsy results stated that "acute intoxication due to the combined effects of cocaine and opiates" caused his death, with coronary artery disease and cardiac hypertrophy (an enlarged heart) as contributing factors. Media coverage of Caminiti's death was almost completely overshadowed by that of actor Christopher Reeve, who also died in New York City the same day as Caminiti.

In 2016, he was posthumously elected into the San Diego Padres Hall of Fame.