Krasinski was born in the Brighton section of Boston, Massachusetts, the son of Mary Clare (née Doyle), a nurse, and internist Dr. Ronald Krasinski He has two older brothers, Kevin and Paul, and was raised Catholic in the suburb of Newton, Massachusetts.[3] He played on the same Little League Baseball team and attended the same high school as B.J. Novak, later his co-star (Ryan Howard) on The Office and also a writer and co-producer on episodes of the show. Krasinski graduated from Newton South High School in 1997. He took the semester off after high school and before college to teach English in Costa Rica. He went to Brown University, where he graduated in Fall 2001 as a playwright — writing an honors thesis titled "Contents Under Pressure". He then attended the National Theater Institute in Waterford, Connecticut.

Krasinski's first stage experience was starring in a satirical play written and cast by B. J. Novak for Newton South High School. Originally going to college to be an English teacher, he decided to continue acting after doing a reading of David Foster Wallace's Brief Interviews with Hideous Men. After college, Krasinski went to New York City to pursue acting, doing commercials and guest spots on television shows, but also doing readings of off-Broadway plays. He also starred in the play "What the Eunuch Saw," directed and written by a former college classmate.

Krasinski spent the 2000 summer as a script intern on Late Night with Conan O'Brien. In addition to his role on The Office, Krasinski's television credits include appearances on Law & Order: Criminal Intent, Without A Trace, Ed, American Dad! (as the voice of a squirrel), and an episode of CSI: Crime Scene Investigation.

His feature film credits include Kinsey, Jarhead, Duane Hopwood, Shrek the Third and The Holiday. He also had cameos in For Your Consideration and Dreamgirls. He wrote and directed a film adaptation of David Foster Wallace's Brief Interviews with Hideous Men (2008).

Filmed before he was on The Office yet released in 2007, he starred as Gideon in A New Wave. Filmed in 2006, he starred as Brevin in Smiley Face with Anna Faris More recently, he had major supporting roles in the films, License to Wed, with Mandy Mooreand Robin Williams and Leatherheads with George Clooneyand Renee Zellweger He is currently filming with Jarhead director Sam Mendes on an upcoming untitled movie co-starring Maya Rudolph and Cheryl Hines. Filming began in April 2008 and is set to end in June, following on location shots in Connecticut, Arizona, and Florida.

Krasinski was featured in People magazine's Sexiest Men Alive issue of 2006. Krasinski narrated a series of commercials for Ask.com starting in March 2006 as well as a commercial for the Apple TV in April 2007. Krasinski appears in posters and online advertisements for Gap for the holidays, and has begun narrating television commercials for Best Buy. Krasinski took the footage of Scranton, Pennsylvania for The Office, including the clips shown in the opening credits.