The second of four children, McGinest attended Long Beach Polytechnic High School, where he garnered all-state honors in football and baseball. 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-CIFSouthern 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.
In Super Bowl XXXIX, McGinest was used in a different manner than his regular role. While he usually lined 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 a 2005 wild card playoff win over the Jacksonville Jaguars, McGinest eclipsed two NFL postseason records—most sacks in a game (4.5) and most career postseason sacks (16), surpassing Bruce Smith.
His 78 career sacks rank third all time for the Patriots.
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.
Following retirement, McGinest joined the NFL Network as a football analyst, and appears on various programs, including NFL Total Access. Prior to joining the NFL Network, McGinest served similar roles at Fox Sports and ESPN.
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 would go on to sponsor a similar event in the Cleveland area with Browns teammates.
McGinest owns an entertainment company in Los Angeles called "55 Entertainment", and has had cameo appearances in television shows such as Arli$$ and The Game, and had a small role as a detective in the film I Tried, with rap group Bone Thugs N' Harmony.