Meloni is Italian on his father's side and French Canadian on his mother's side. Originally from Washington D.C., he attended St. Stephen's School (now St. Stephen's and St. Agnes School) and the University of Colorado at Boulder, where he first began studying acting, graduating in 1983.

After graduation, Meloni went to New York where he continued his studies with Sandford Meisner at the famed Neighborhood Playhouse. Meloni and his wife Sherman (a production designer) share residences in New York and Los Angeles. Christopher and Sherman have two children: daughter Sophia Eva Pietra, b. March 23, 2001, and son, Dante Amadeo, b. January 2, 2004.

Meloni worked as a construction worker prior to getting his acting break. He earned a degree in history at the University of Colorado. Meloni started his acting career at the University of Colorado at Boulder, where he did his undergraduate studies. He has also worked as a bouncer, bartender, and personal trainer. Meloni is best known for his role as Detective Elliot Stabler in the TV series Law & Order: Special Victims Unit.

Meloni worked his way up the acting ladder with short-lived TV series and bit parts in a number of films. His first noticeable role was as the hotheaded son of a Mafia Don in the 1996 lesbian thriller Bound. He also appeared as Julia Roberts' fiance in Runaway Bride. His first real moment of stardom came from his controversial role as bisexual sociopath Chris Keller in the HBO prison drama Oz. The role called for him to passionately kiss and touch other men, frequently submit to rear and full frontal nudity, and even urinate into a bucket. Meloni's raw magnetism and affable reaction towards the open sexuality of his character earned him press attention and legions of fans, particularly within the gay community. In 1999, he even jokingly kissed his onscreen partner Lee Tergesen at an awards dinner for GLAAD. L&O producer Dick Wolf, impressed by Meloni's acting abilities, signed him up for SVU in 1999, where he has remained ever since. From 1999 to 2003, he appeared on both shows simultaneously. He even showed off some considerable comedic muscle when he portrayed the character "Gene" in Wet Hot American Summer in 2001, and the character of "Freakshow" (albeit in heavy make-up) in the 2004 comedy Harold & Kumar Go to White Castle.