Born in Ponce, Puerto Rico, Santiago came up to the major leagues in 1987 with the San Diego Padres and he established a Major League record that year for a rookie by hitting safely in 34 straight games. He won the National League's Rookie of the Year Award unanimously that year.

Santiago may not have matched all the hype that subsequently followed him, but he has made his mark in baseball and in catcher history. He joined the Marlins in 1993, who traded him to the Reds, where he briefly recovered his best form. Bouncing in 1996 to the Phillies (where he became the first player to hit a grand slam off Greg Maddux, who has allowed only two in his career) he hit home runs in four consecutive at-bats. He then went to the Blue Jays (1997-98) where he lost almost the entire 1998 season to a serious injury sustained in a car crash in Florida. A free agent again, he played 89 games for the Cubs before arriving in San Francisco in 2001, where he helped his team to the playoffs in 2002. His good hitting continued in the playoffs, where he was named 2002 National League Championship Series MVP. Highlights of Santiago's career include a 272-game catching streak with no passed balls, 4-time All Star player from 1989-1992, and 3-time Gold Glove winner 1988-1990. He made it to post season four times including one World Series in 2002. In San Francisco on 5 April 1993, Santiago hit the first home run ever by a Florida Marlin.

Santiago now holds the #7 all-time baseball record of most games caught in a career (1,917). Providing he is picked up by a team for the 2006 season, he may very well be able to catch two more games to put him ahead of Al Lopez and eleven more to pass Carlton Fisk as the #5 position (1,927). Santiago is the only active player in the top 10.

In 2003, Santiago was named by FBI investigators as one of the athletes alleged to have received anabolic steroids, via the Bay Area Laboratory Co-operative (BALCO). In 2004, Santiago, again a free agent, signed with the Kansas City Royals and had his season cut short after sustaining injuries that sent him to the disabled list. After the 2004 season, the Royals traded him to the Pittsburgh Pirates for Leo Nunez, a rookie pitcher. The Pirates let Santiago go after a mere 23 at-bats in favor of giving playing time to young David Ross. Santiago signed with the New York Mets to a AAA minor-league contract, but he appeared in only a handful of games. He opted out of his AAA contract and intends to play in the 2006 season.

With his career almost certainly over, discussions have arisen about where he ranks among the game's all-time catchers. His main claim to fame is his excellent durability, which has allowed him to post productive numbers late in his career, at an age when most catchers are already retired.