He played in Major League Baseball (MLB) from 1897 through 1900 for the Baltimore Orioles, Pittsburgh Pirates, and New York Giants.

He reached the majors in 1897 with the Baltimore Orioles, spending one and a half years with them before moving to the Pittsburgh Pirates (1898), New York Giants (1899), and again with Pittsburgh (1900).

In a four-season career, O'Brien was a .278 hitter (436-for-1569) with 10 home runs and 229 RBI in 427 games.

O'Brien died in Phoenix, Arizona at the age of 27, from pneumonia resulting from lung disease.

He believed his disease was caused by his drinking a large amount of salty seawater after having been told that it would cure his seasickness.