The second of three children, McGinest attended Long Beach Polytechnic High School, where he garnered all-state honors in football and basketball. In football, he earned All-American recognition from Super Prep, Blue Chip and Tom Lemming magazines and was selected to several all-star teams, earning all-city, all-state, and all-region honors as a linebacker in 1989. He totaled 107 tackles, including 18 sacks, two fumble recoveries, four passes defensed, including an interception, and blocked four kicks as a senior. In 2009, McGinest was elected to Poly's Football Hall of Fame.  On the court, he earned Long Beach Press-Telegram "Best in the West," All-CIF Southern Section and all-league honors while averaging 14 points per game during the 1989-90 season.
From 1990 to 1993, McGinest played football at the University of Southern California. He wore number 55. McGinest earned all-conference honors three straight years and All-American acclaim. During his senior year, he was a Lombardi Award finalist, and earned All-American and All-Pac-10 conference honors. He started every game at weakside defensive end for the Trojans. McGinest finished his collegiate career with 193 tackles (134 solos), 29 sacks (171 yards), 48 tackles for loss (238 yards) and 26 passes batted away. McGinest received a degree in public administration from USC in 1994.
McGinest was drafted by the New England Patriots in the first round (fourth overall) of the 1994 NFL Draft. He was one of the cornerstones for New England's success in winning the Super Bowl in 2001, 2003, and 2004. He was named to the Pro Bowl twice, in 1996 and 2003.
In Super Bowl XXXIX, McGinest was used in a different manner than his regular role. While he usually lines up as an outside linebacker in a 3-4 scheme, the Patriots moved him to the defensive line as a defensive end in an effort to keep Philadelphia quarterback Donovan McNabb from scrambling.
In the 2005 wild card game, which the Patriots won 28-3, against the Jacksonville Jaguars, he set an NFL postseason record by recording 4.5 sacks in one game as well as breaking Bruce Smith's record for the most all-time sacks in the postseason with 16. His 78 career sacks rank third all time for the Patriots. The Patriots released McGinest on March 9, 2006.
On March 15, 2006, McGinest signed with the Cleveland Browns, reuniting with head coach Romeo Crennel, who was the Patriots' defensive coordinator during McGinest's stint in New England. McGinest signed a three-year deal worth $12 million with $6 million in guarantees and bonuses. McGinest stated in an interview prior to the 2008 season that he would be playing his final year of professional football before retiring in the offseason. In July 2009, McGinest stated that he would like to end his career with the Patriots.
McGinest established the Willie McGinest Freedom School, a program which aims to provide social and cultural enrichment for neighborhood youth. On May 3, 2005, the city council of Long Beach declared that every year, May 3 will be recognized as Willie McGinest Day in recognition of his charitable efforts and civic involvement. During the 2004 holiday season, McGinest sponsored "Shop with a Jock," an event that gave 50 Boston-area children the opportunity to go on a $100 shopping spree with him and his teammates. He has since sponsored a similar event in the Cleveland area with Browns teammates.