An All-Pro and four-time Pro Bowl selection, Bruce amassed 15,208 receiving yards in his career (fifth all-time).

In accomplishing this feat, Isaac Bruce surpassed former Houston Oilers WR Charley Hennigan's 34-year-old record of 1,746 set in 1961.

Bruce made USA Today's All-Joe team, All-Madden, and All-Pro by Sports Illustrated and he was voted a first alternate to the Pro Bowl.

Prior to his injury in 1998 in a home game against the Minnesota Vikings, Bruce had 11 catches for 192 yards and an 80-yard touchdown.

Bruce caught Kurt Warner's 73-yard touchdown pass late in the fourth quarter of Super Bowl XXXIV to give the Rams a 23–16 lead, which turned out to be the game winner.

He became the first Rams receiver to earn back-to-back Pro Bowl invitations since Henry Ellard accomplished the feat for the 1988 and 1989 seasons.

That same year, Bruce and teammate Torry Holt became only the second WR duo from the same team to each gain over 1,400 yards in the same season (see Herman Moore and Brett Perriman).

Bruce became the Rams' all-time leader in receptions in 2002 while posting his fourth consecutive 1,000-yard receiving season.

Luckily for Bruce, he scored a game-winning touchdown and the game is almost forgotten because of 34–34 tie between the Falcons and Steelers the same day.

That year Bruce made seven receptions for 116 yards in the NFC Divisional Playoff Game vs. Carolina on January 10, 2004, making him the only Rams player to have four career 100-yard postseason performances, breaking a tie with Tom Fears.

He started the season with four consecutive 100-yard receiving performances, the first player to accomplish this feat since Houston's Charley Hennigan in 1963.

With the retirement of Jerry Rice, Bruce entered 2005 as the NFL's active leader in career receiving yards; a foot injury caused him to miss 5 games, and he was passed by Marvin Harrison by the end of the season.

In Week 15, he retook the lead in career receiving yards among active players from Marvin Harrison, and in the same game passed James Lofton to become third on the all-time list.

[11] On February 29, 2008, Bruce signed a two-year, $6 million contract with the San Francisco 49ers, to reunite with his former offensive coordinator Mike Martz.

[13] On December 21, 2008, in a game at St. Louis against his former team, the Rams, Bruce caught his 1,000th career reception – a 3-yard touchdown catch.

After contemplating retirement in the offseason, he elected to return to the 49ers in 2009 for his 16th season,[14] reasoning that he was there to "get in the playoffs again and win a Super Bowl".

[19] Bruce is nicknamed "The Reverend" because he wished to become one after he finished his football career; he also wanted to become a substitute teacher.