Born in Waynesboro, Pennsylvania, to Elizabeth and Ed McCaffrey, McCaffrey played high school football at Allentown Central Catholic High School in Allentown, where he competed in the East Penn Conference in Pennsylvania’s Lehigh Valley. McCaffrey was also a standout basketball player for Allentown Central Catholic High School, leading the school to state titles in 1984 and 1986.

He played college football at Stanford University in California, and as a senior in 1990 was an All-American. At Stanford, he was a member of the Sigma Alpha Epsilon fraternity.

McCaffrey was selected by the Giants in the third round (83rd overall) in the 1991 NFL draft. During his thirteen-year career, he won three Super Bowl rings (Super Bowl XXIX, as a 49er; XXXII and XXXIII, as a Bronco) and made a Pro Bowl appearance in 1998. In Denver, he became a reliable target for quarterback John Elway, set a Broncos record for most receptions in a season (with 101 receptions in 2000), and had an exceptional performance in Super Bowl XXXIII, recording five catches for 72 yards. Also in 2000, McCaffrey and teammate Rod Smith became only the second wide receiver duo from the same team to each gain 100 receptions in the same season (see Herman Moore and Brett Perriman).

In the opening game of the Broncos’ 2001 season, McCaffrey suffered a leg fracture while playing a Monday Night Football game with the Broncos against the Giants. He rebounded in the 2002 season with 69 receptions and 903 yards. Hampered by injuries during a disappointing 2003 season, McCaffrey retired on February 29, 2004. He finished his career with 565 career receptions for 7,422 yards along with 55 touchdowns.

McCaffrey began coaching youth football camps in the summer of 2000. In 2011, he founded SportsEddy, which includes not just football but lacrosse, soccer, baseball and basketball camps. The Ed McCaffrey “Dare to Play” football camp and the “Dare to Cheer” cheerleading camp for individuals with Down syndrome are produced in partnership with the Global Down Syndrome Foundation. McCaffrey also founded the McCaffrey Family Foundation with wife Lisa, to assist children whose medical situation has created an academic or financial hardship.

He also has his own brand of mustard and horseradish sauce, which can be found in supermarkets across Colorado and into Nebraska. On July 30, 2012, McCaffrey was named the new color analyst for 850 KOA, flagship station of the Denver Broncos Radio Network, replacing Brian Griese. On January 7, 2019, it was announced he would serve as the commissioner of the Pacific Pro Football league, a planned professional development football league founded by Don Yee.

Dylan McCaffrey was a four-star quarterback for Valor Christian High School who graduated in 2017. His team won the Colorado Class 5A state championship (5A being the highest of the 5 classes) 3 of the 4 years he played. As the second-ranked quarterback in the country and top-ranked quarterback in Colorado, Dylan received scholarship offers from Duke, Colorado, Rutgers, LSU, Michigan, Washington, UCLA, Colorado State and Penn State. He committed to play college football at Michigan in February 2016.

McCaffrey was named the head football coach at Valor Christian High School in February 2018.

On December 12, 2019, the University of Northern Colorado hired McCaffrey as head football coach.

The youngest son, Luke McCaffrey, is a 2018–2019 senior at Valor Christian High School, he graduated in May 2019. Luke has also received an offer from Michigan, along with an offer from Nebraska. He committed to Nebraska in June 2018.