At the age of 23, Walt made his first major league appearance for the Oakland Athletics in September . The club was impressed enough with the young shortstop's talent that they traded starter Alfredo Griffin that December, ensuring Weiss would assume a starting job in the 1988 season. Weiss' 1988 season did not seem very impressive offensively as he batted .250 with three home runs, 39 RBIs and 44 runs scored, but the budding shortstop's defensive wizardry helped lead the A's to their first American League pennant since . The 1988 World Series was a rematch of the 1974 matchup, with the Los Angeles Dodgers winning the National League pennant. Weiss made a costly error in Game Four of the matchup that allowed the Dodgers to win the Series in five games. Following the season Weiss was awarded the American League Rookie of the Year Award, becoming the third consecutive Oakland player to win the award, following José Canseco and Mark McGwire. He was also selected for the 1988 Topps All-Star Rookie Roster.
Limited by previous injuries, Weiss did not play much in as Oakland missed the playoffs for the first time since 1987. In what would be his final year in Oakland, Weiss batted an anemic .212 in and was traded to the newly-formed Florida Marlins during the offseason.
Weiss played in 158 games in for the Marlins, but following the season he became a free agent and chose to sign with the Colorado Rockies - which also had begun play in 1993. He became the first player to play for both the expansion Marlins and Rockies. Weiss had four modestly successful years playing for Colorado, posting career highs in home runs (8) and RBIs (48). However, his strengths were solid defensive play at shortstop and his ability to get on base (.351 lifetime OBP).
However, in Game 3 of the 1999 NLDS against the Houston Astros, Weiss made a stunning defensive play to save the season. In the bottom of the tenth, with the bases loaded, one out, and the score tied, Tony Eusebio hit a sharp grounder right up the middle. Weiss ranged hard to his left, dove to his stomach, and threw to home to get the force out. After the game, Weiss said that the ball nearly ripped the glove off his hand. Weiss and the Braves went on to win the game, and the series, on the way to an appearance in the 1999 World Series.
In 2000, Weiss only had 192 at-bats, mostly due to losing playing time to the emergent Rafael Furcal, who would go on to win the Rookie of the Year Award, just like Weiss twelve years prior. Following the season, Weiss retired.