Santiago attended St. Michael's College School, before moving on to Kent State University from 1992 to 1996. He caught 62 passes for 730 yards for an 11.8 career average with four touchdowns during his career at Kent State.
He started 22 of 33 career games at Kent State and was named to the MAC All-Academic first-Team for three straight seasons.
Santiago was selected by the Atlanta Falcons in the third round (70th overall) of the 1997 NFL Draft. He also was selected by the Edmonton Eskimos in the fifth round (40th overall) of the 1997 CFL Draft.
During his first year, he totaled 217 receiving yards in eleven games, for an average of 12.8 yards per catch. In 1998, Santiago contributed to the team reaching the Super Bowl, posting 27 receptions for 478 receiving yards and 5 touchdowns in 16 games, for an average of 15.9 yards per catch. He is famously known for popularizing a dance to celebrate a touchdown in which he flapped his arms as if they were wings and rhythmically bouncing side-to-side in the crowd's direction. The dance later became known as the "Dirty Bird".
On August 27, 2000, he was traded to the Dallas Cowboys in exchange for a 2001 fourth round selection (#102-Matt Stewart) and a 2002 seventh round selection (#217-Michael Coleman). The Cowboys acquired him to backup David LaFleur and Jackie Harris, but he was cut on November 21.
On November 22, 2000, he was claimed off waivers by the Cleveland Browns, where his receiving yardage went down. He wasn't re-signed after the season.
On July 15, 2002, he was signed as a free agent by the Minnesota Vikings, but injured his foot and knee in training camp and was waived injured on August 27.
On March 8, 2003, he signed with the Oakland Raiders, where he played in 12 games (starts), with 5 receptions for 69 receiving yards, and averaging 13.8 yards per catch. Having already totaled 972 yards before joining the Raiders, he was able to reach the 1,000 yard milestone during his short tenure with the Northern California team.
On April 15, 2004, Santiago was signed by the Denver Broncos who released him at the end of training camp on August 31.
On May 23, 2006 Santiago re-signed with the Oakland Raiders after not suiting up the 2005 season, but was waived injured on September 9. On December 13, 2006, he signed with the New England Patriots, who released him 2 days later after injuring his foot.
On August 7, 2007 The Oakland Raiders signed O. J. Santiago. However, he was released by the Raiders before the 2007 season began.
In his career in the NFL, he played in 68 games, gaining a total of 1,041 yards for an average of 12.9 yards per catch and 9 touchdowns.
On May 14, 2010, he signed as a free agent with the Montreal Alouettes of the Canadian Football League (CFL). He was released on August 28.
Santiago currently serves as an Assistant Football Coach at Kent State University.