Egglesfield was born in Farmington Hills, Michigan, the second child of Kathleen (née Dineen) and William Egglesfield, a physician. His mother is Irish. He has two siblings: an older sister, Kerry, and a younger brother, Sean. He was brought up in a Catholic household.
Egglesfield spent his early childhood in the Metro Detroit area. At the age of ten, he and his family moved to Morris, Illinois, a small community south of Chicago. Growing up, he was more studious than rambunctious, preferring to spend Friday nights alone building model airplanes. His dream was to follow his father's footsteps as a physician, but became interested in acting watching his older sister Kerry perform.
Shy in his adolescent years, he credits his prep football coach, Dave Mattio, with helping gain a positive self-esteem. After Egglesfield graduated from Marian Catholic High School in Chicago Heights, he attended Illinois Wesleyan University and played for the football team. He transferred to the University of Iowa, where he was in the pre-med program. After he received his BS from Iowa he backpacked throughout Europe.
To earn money for medical school, Egglesfield turned to modeling. He won a contest (he entered at the urging of a friend), and soon after, he left medicine behind for a modeling career. He is signed with Beatrice Model agency in Milan, Italy, and DNA Model Management in New York City. He modeled for Versace, Calvin Klein, and Armani, among others before he started acting. In the late 90's, he was featured on the covers of Italian Vogue (shot by Steven Meisel) and L'Uomo Vogue (twice, photographed by Bruce Weber and Ellen Von Unwerth respectively).
After taking drama classes, Egglesfield found himself guest starring on television series such as Law & Order: Special Victims Unit, The $treet, Gilmore Girls, Charmed, and Nip/Tuck. He also had a small role in the 2005 film Must Love Dogs, in addition to many other minor film projects. On September 26, 2005, he made his debut on All My Children, taking over the role of Josh Madden from his short-lived predecessor Scott Kinworthy. In 2005, Egglesfield was named one of People magazine's "Sexiest Men Alive". In 2006, he attended the Cackalacky Film Festival in Charlotte, N.C., where his film Beautiful Dreamer was awarded Best American Full Feature Film.
Beginning in the fall of 2009, Egglesfield portrayed chef/surfer guy Auggie Kirkpatrick in CW's 2009 series Melrose Place. However, due to a change in the direction of the show, Eggelesfield and his co-star Ashlee Simpson-Wentz were fired and his character was written out of the show during the thirteenth episode. In 2011, he starred in the film adaptation of Something Borrowed opposite Kate Hudson. As of August 2011, Egglesfield plays the recurring role of Tommy Rizzoli on TNT's Rizzoli & Isles. From 2012 to 2013, he starred as Evan Parks on the Lifetime drama series The Client List.
He owns and runs his own New York City-based clothing company Shout Out Clothing!, which he principally uses as a vehicle to promote and support educational initiatives such as Project Grad, and also "Stay in school" programs.