He played in Major League Baseball (MLB) for the Oakland Athletics, Toronto Blue Jays, Seattle Mariners, Los Angeles Dodgers, San Francisco Giants, and Miami Marlins.

[5] Toward this end, the Venditte backyard included astroturf, a batting cage, a radar gun, and a pitching machine.

Creighton head coach Ed Servais did not allow Venditte to pitch with both arms during his five appearances his freshman year, fearing the spectacle would become a "circus".

Starting with his sophomore season, Venditte regularly used both arms in collegiate play; he posted a 3.02 earned run average (ERA) in 62+2⁄3 innings pitched.

[13] On June 8, 2007, the New York Yankees selected Venditte in the 45th round of the 2007 Major League Baseball draft with the 1,345th overall pick.

Venditte was surprised by the pick, because he had told all major league scouts that he intended to return to Creighton for his senior year.

[13] Venditte said that he was not quite ready to turn professional and wanted to build velocity with his left arm and add another pitch with his right.

[14] On June 19, 2008, in his first minor league appearance with Staten Island against the Brooklyn Cyclones, Venditte pitched a scoreless ninth inning for a Yankees win.

After this had happened several times, the teams appealed to the umpiring crew, which ruled that the batter must first select from which side of the plate he intended to hit, and that the pitcher would then be allowed to declare with which arm he would pitch.

(The Venditte Rule, adopted several weeks later by the umpires' association, would make the opposite determination and preserve the traditional right of a switch-hitter to choose an opposite-handed match-up.)

A film of the incident received notoriety on the Internet and the tale was recounted in a number of places, including within the baseball compendium Rollie's Follies.

Venditte pitched for the Yankees in a spring training game against the Atlanta Braves on March 30, 2010, giving up one earned run on two hits and a walk in 1+1⁄3 innings.

[26] Though Venditte had excellent minor league numbers, he was not considered a top prospect because of his age and, scouts believed, underwhelming fastball velocity.

During the offseason, he signed a minor league contract with the Oakland Athletics, receiving an invitation to spring training in 2015.

[30] Venditte began the 2015 season with the Nashville Sounds of the Class AAA Pacific Coast League (PCL).

[31] He pitched to a 1.36 ERA with 33 strikeouts in 17 games for Nashville before he was promoted to the Athletics for his first major-league stint on June 5.

[34] The East Oregonian, a newspaper published in Pendleton, Oregon, mistakenly described the ambidextrous Venditte's first MLB appearance as "Amphibious Pitcher Makes Debut".

[48] On March 12, 2017, the Mariners traded Venditte to the Philadelphia Phillies in exchange for minor league player Joey Curletta.

[49] He spent the 2017 season with the Lehigh Valley IronPigs of the International League,[50] making 52 appearances out of the bullpen and registering a 9–5 record and 3.36 ERA with 69 strikeouts in 69+2⁄3 innings pitched.

On January 6, 2020 Venditte signed a minor league contract with the Miami Marlins, with an invitation to spring training.

After receiving little interest from teams in spring 2021 after becoming a free agent, Venditte "took that as writing on the wall", he said, to work full time for a Peoria, Illinois, company.

Despite batting left-handed, he is exclusively right-handed when performing tasks such as swinging a golf club, writing, or eating.

[6] Mizuno has custom-made six-fingered gloves for Venditte since the age of seven with a thumb-hole on each side, allowing him to easily switch back and forth.

After consulting with a variety of sources, including the Major League Baseball Rules Committee, the PBUC issued its new guidelines on July 3, 2008.