He played 15 seasons in Major League Baseball (MLB) between 1995 and 2009 for the Milwaukee Brewers, Houston Astros, San Diego Padres, Boston Red Sox, and Los Angeles Dodgers.

Loretta was traded to the Houston Astros during the 2002 season for Keith Ginter and Wayne Franklin, and played in 21 games as a reserve before filing for free agency.

His .335 average ranked him third in the National League batting race behind Barry Bonds (.362) and Todd Helton (.347), and he also joined Tony Gwynn as the only San Diego players to have 200 hits in a regular season.

In 2005, Loretta hit .280 with three home runs and 38 RBI in 105 games with the Padres, after he had surgery to repair a strained ligament in his left thumb.

[5] On June 29, 2007, with 2 outs and behind one run, the Colorado Rockies intentionally walked Carlos Lee who had hit a walk-off grand slam the night before.

[6] On October 8, 2009, Mark Loretta hit a walk-off single to defeat the St. Louis Cardinals, 3–2, in game two of the National League Division Series.

The score was tied and the bases were loaded with two outs when he stroked a line drive off Cardinal reliever Ryan Franklin to center fielder Colby Rasmus.

[12][13] Israel lost to Spain in extra innings in the Pool Finals, missing out on a spot in the World Baseball Classic.

[13][14][15] Loretta attended Saint Francis High School in La Cañada, California, and he was a classmate of Gregg Zaun.