Famiglietti was born in Providence, Rhode Island. He was raised in Clinton, Connecticut, where frequent family trips to the Goodspeed Opera House sparked his interest in performing. However, it was not until his teen years that he shifted to the other side of the footlights in Goodspeed's "An Evening with Max Showalter and Friends" and won the Goodspeed Guild Musical Theatre Award for his performance. In high school, he was class president in his junior and senior years, captain of the baseball team, a member of the band and chorus and co-announcer of school football and basketball games. On winning a small part in his school's production of Guys & Dolls he added drama classes to his curriculum and began to exercise acting and singing muscles. Leading roles followed in local theater productions of "Bye, Bye Birdie" and "The Music Man" and school plays including "Kiss Me Kate" and "Once Upon a Mattress."
Mark attended New York University as a drama major, where he studied with the Atlantic Theatre Company. During his second semester, he put college on hold and headed for Hollywood after being cast as Nick Hammer, on the NBC series Hang Time. He also guest-starred on The WB comedy Zoe, Duncan, Jack & Jane, landed the role of Scout on the short-lived WB series Young Americans and co-starred as a friendly bartender in the February-slated TV movie A Tail of Two Bunnies starring Marilu Henner and Rhea Perlman. In 2002 and 2003, he appeared in We Were the Mulvaneys and Fullride and he had a role in the blockbuster movie Terminator 3: Rise of the Machines playing Claire Danes' fiancée, named "Scott Mason."
After being involved in Terminator 3, Famiglietti finished his first screenplay (Chasing Fate). The movie is a romantic comedy where a wealthy young man kicks his fiancée to the curb, only to watch her ascend to fame and fortune while his life falls apart. Actors Jordana Brewster and Kip Pardue were set to star in the film, however, financing was never secured. He also wrote another screenplay called Succubus, an action-comedy movie about a guy who decides to set out and bring a succubus (a female demon who seduces men and steals their souls) down; after discovering that his nerdy best friend is dating her. The project was set up at MGM, with Mark Steven Johnson attached to direct. However, Sony bought MGM and the project was never made. In 2005 he appeared in 9 episodes of ABC's Eyes, but only the first 5 were aired because the show was cancelled. The show subsequently ran four years later in its entirety on Direct TV's 101 network from September to December 2009. Mark also played an assistant district attorney in CBS pilot Conviction which also starred Sally Field and Eriq LaSalle. The show was not picked up. Mark Famiglietti appeared in Nobel Son and Bottle Shock, both for director Randall Miller who also directed Mark in The Tale of Two Bunnies a decade earlier. Those indie films both feature Alan Rickman, Eliza Dushku, and Bill Pullman.
In 2008, he appeared on the Without a Trace episode "Rewind". He also does his voice role in the upcoming film BIONICLE: The Legend Reborn. In 2009, Famiglietti began a recurring role on the ABC series FlashForward. The series was cancelled in May 2010 after he had filmed multiple episodes opposite Tony Award winner Brian O'Bryne. In 2010, Famiglietti began filming opposite 50 Cent, Val Kilmer and James Remar for the indie movie GUN to be released in 2011. In late 2010, Famiglietti filmed the "Untitled Josh Berman Pilot" playing Jamie-Lynn Sigler's fiance. Other cast members include Lou Diamond Phillips and Sherry Stringfield. In the summer of 2011, Famiglietti filmed Live at the Foxes Den opposite Jackson Rathbone, Jocelin Donahue, Carly Craig, Pooch Hall, Caity Lotz and Jack Holmes who co-wrote the screenplay with Michael Kristoff. Immediately following, Famiglietti began production on the movie Stealing Roses opposite John Heard, Cindy Williams, Bruce Davison and Josie Davis for director Megan C. Johnson from her original screenplay. In April 2012, "Stealing Roses" won "Best of the Fest" at the LA Comedy Fest. In late summer of 2011, Famiglietti shot the movie Acting Like Adults playing the lead role of "Brett." In December 2011, Mark was reunited with his fellow Terminator star Kristanna Loken, shooting a cameo in the movie "Dark Power."
In the spring of 2012, Mark began shooting the movie Home for Christmas opposite Shantel VanSanten, Rob Mayes, Nikki DeLoach and Orson Bean in a family comedy directed by Michael Feifer which was later aired on television as Golden Christmas 3 in 2012. Later that summer, Famiglietti began work on an independent romantic-comedy titled March Sisters at Christmas. An update of Little Women, the cast includes Julie Berman, Justin Bruening and Kaitlin Doubleday. The movie was bought by Lifetime during the 2012 holiday season and set over the course of multiple years. Mark appeared in episode 9 of the fifth season of Mad Men playing "Bernie Rosenberg." In 2013, Famiglietti booked the lead role in the feature Secrets of a Psychopath opposite Kari Wuhrer for director Bert I. Gordon. Having written, directed and produced over 30 feature films, he was bestowed with a Saturn award in 2011 for his body of work. Later that summer, Mark was added to the cast of Christmas Belle alongside Haylie Duff and C. Thomas Howell. In late 2013, Famiglietti was cast as one of the male leads opposite Cary Elwes, Ruth Bradley and Meg Chambers Steedle in the USA Network pilot "Horizon" produced by Gale Anne Hurd. In 2014, the network decided not to pick up the pilot to series. Famiglietti has made regular, recurring and guest appearances totaling over 60 episodes in television shows such as Mad Men, How to Get Away with Murder, Castle, Grimm, FlashForward, Drop Dead Diva, Eyes, Fastlane, CSI: NY, CSI: Miami, CSI: Crime Scene Investigation, Without a Trace, and Bones among others.