He played Major League Baseball from 1995 to 2001 for the Montreal Expos, San Francisco Giants, Los Angeles Dodgers, and Oakland Athletics.

A native of El Dorado Hills, California, Santangelo attended Oak Ridge High School, Sacramento City College, and the University of Miami.

[2] Santangelo made his Major League debut on August 2, 1995, as the starting left fielder against the Florida Marlins.

He signed as a free agent with the San Francisco Giants on December 23, 1998, and played in 113 games for them during the 1999 season, hitting .260.

In his tenure with the Dodgers, Santangelo primarily was used as a backup to Gary Sheffield, Tom Goodwin and Todd Hollandsworth.

Santangelo, a switch hitter, hit home runs from both sides of the plate in the same game on June 7, 1997, against the Chicago Cubs.

[5] Santangelo co-hosted a sports radio talk show called "The Rise Guys" on KHTK-1140 AM in Sacramento from 2006 to 2008.

After Santangelo's first season as a broadcaster with the Nationals, The Washington Post sports columnist Tracee Hamilton noted that the Carpenter-Santangelo team improved over 2011,[6] and The Washington Post sports blogger Dan Steinberg wrote about Santangelo's performance and how he sought to be educational, not outrageous, in the broadcast booth.

[8] He was able to use the line in every game he called with the team, with the closest he came to not be able to say it was when Michael Wacha was an out away in September 2013 before Ryan Zimmerman broke up the bid with an infield single.

In 2023, Santangelo teamed up with Joe Ritzo to fill in for Jon Miller and Dave Flemming on KNBR for Giants broadcasts.

Santangelo said KNBR Tonight was canceled due to budget cuts, and would be replaced with syndicated programming.

[11][13] In a statement on May 8, Santangelo denied the allegations,[11][13] and a MASN spokesman expressed surprise at the Nationals' willingness to air the accusations publicly before MLB could complete an investigation.

[14] Following the release of the Mitchell Report in which he was named by Kirk Radomski as having used Deca-Durabolin, HGH, and testosterone, Santangelo confirmed he used HGH on two occasions in 1997 and 2000 to rehab from a quadriceps and knee injury but denied the other allegations, including telling teammate Adam Piatt that Radomski "will get you what you need.