Prior to the 2003 season, Harrison was named a defensive captain in his first year with the Patriots by the coaching staff after Lawyer Milloy was released.

On January 10, 2004, in the divisional playoff game against the Tennessee Titans, he intercepted Steve McNair, which set up Antowain Smith's touchdown, as New England would hold on for a 17–14 win.

Harrison then went on to help the New England Patriots win their second title in three years, against the Carolina Panthers in Super Bowl XXXVIII, 32–29.

He fractured his right arm late in the game, but a Tom Brady-led drive and Adam Vinatieri field goal secured the Patriots' victory.

The next week in the AFC Championship, Harrison jumped a Ben Roethlisberger pass and took it 87 yards for a touchdown, helping the Patriots defeat the Pittsburgh Steelers, 41–27.

[6] Harrison, in Super Bowl XXXIX, would record seven tackles, a sack, and two interceptions of quarterback Donovan McNabb, despite missing almost an entire quarter due to an injury sustained during the game.

The 2005 season began a string of multiple injuries for the 12th-year safety, with Harrison's season coming to an end on September 25 against the Pittsburgh Steelers, when he was hit in the knee by a falling Cedrick Wilson and tore the anterior cruciate, medial collateral, and posterior cruciate ligaments in his left knee.

[7] After sporadic playing time in the preseason, Harrison started the first seven of the Patriots' games in 2006, totaling 23 tackles and one sack.

Harrison was suspended for the first four games of the 2007 regular season for admitting to federal investigators that he knowingly obtained and used human growth hormone (HGH).

[8] Harrison stated to the media that he used "a banned substance" for "accelerating the healing process from injuries [he] sustained playing football," and "never to gain a competitive edge.

I put a foreign substance in my body and don't know the long-term effects," he said on Football Night in America.

In the play, a long forward third down pass by Eli Manning over midfield, Harrison was both attempting to block reception and tackle at the same time.

Harrison was the player during a preseason game against the then St. Louis Rams who hit Rams QB Trent Green low, resulting in a season-ending knee injury for Green, ironically thrusting back-up and then relatively unknown QB Kurt Warner into the starting position.

The Rams went on to win the Super Bowl that year and Warner was named NFL MVP and has been inducted into the Pro Football Hall of Fame.