Byrnes began his career in 1994 as an intern with the Cleveland Indians. He rose to scouting director in 1998 and then joined the Colorado Rockies as assistant general manager after the 1999 season. He moved to the Boston Red Sox as assistant general manager in 2003 and was with the team in 2004 when they won their first World Series title since 1918. Byrnes was executive vice president and general manager of the Arizona Diamondbacks (2005-2010) and the San Diego Padres (2011-2014). He joined the Dodgers in 2014.
Byrnes grew up in Washington, D.C., where he attended and played second base for St. Albans School, breaking the single season hits record. He was recruited by Haverford College, where he was team captain and set records for home runs and RBI.  He graduated in 1992 with a BA in English.
Byrnes joined the Cleveland Indians in 1994 after a chance meeting at a Haverford College Alumni game with Ronald M. Shapiro, the father of Mark Shapiro, the team's general manager. He quickly worked his way up the organizational ladder, first as an intern, then as a video scout, and then to the position of Scouting Director in 1998. The Cleveland Indians won the American League Championship Series and advanced to the World Series in 1995 and 1997, as well as won Central Division titles in 1995, 1996, 1997, 1998 and 1999.
Boston Red Sox
Byrnes joined the Boston Red Sox as assistant general manager in 2003 when he was recruited by the team's general manager, Theo Epstein. In his second season with the Boston Red Sox, the team won the 2004 World Series. It was the Red Sox' first World Series championship since 1918, ending what remains the third longest championship drought in the history of any Major League team, after the Chicago White Sox (1917–2005) and the Chicago Cubs (1908–2016).
Byrnes joined the Arizona Diamondbacks as general manager in 2006, where he remained until July 1, 2010. He promoted A.J. Hinch to manager in 2009, a move considered unorthodox because of Hinch's prior position in player development. It was rumored that Byrnes was asked to resign when he was unwilling to fire Hinch.  According to a 2016 story about Hinch by Ken Rosenthal of Fox Sports, Byrnes “actually was ahead of his time.” In the story, Rosenthal noted, “How did it work out for the industry, which reacted to the DBacks’ hiring of Hinch with almost universal disgust? I was one of many in the media who was critical of the move and Byrnes’ framing of it. But the rationales that made Hinch's hiring so controversial are now almost standard, barely drawing notice today.” 
San Diego Padres
Los Angeles Dodgers
In 2014, the Los Angeles Dodgers announced Byrnes as the team's senior vice president of baseball operations. He was recruited by Andrew Friedman, the team’s new president of baseball operations. The new front office was “a force to be reckoned with” according to a story on Los Angeles’ ABC 7's website by Ramona Shelburne, who documented their meetings during the 2014 MLB Winter Meetings. The Dodgers won the National League pennant, advancing to the World Series, in 2017 and 2018. In 2017, the Dodgers finished the season with a major league best 104 victories.
- "Josh Byrnes, senior vice president, baseball operations". mlb.com. Dodgers. Retrieved January 7, 2019.
- Edes, Gordon (April 17, 2005). "Byrnes a rising star on deck". Boston.com. Boston Globe. Retrieved January 7, 2019.
- "Padres' Byrnes setting fresh course". sandiegouniontribune.com. San Diego Union-Tribune. November 26, 2011. Retrieved January 7, 2019.
- Henderson, John (July 3, 2000). "Secret weapon: assistant GMs". DenverPost.com. The Denver Post. Retrieved January 7, 2019.
- "White Sox History". Chicago White Sox.
- "Cubs Postseason Results". Chicago Cubs.
- Edes, Gordon (April 17, 2005). "Byrnes a rising star on deck". Boston.com. Boston Globe. Retrieved January 6, 2019.
- Polishuk, Mark (July 1, 2010). "Diamondbacks Fire Josh Byrnes And A.J. Hinch". mlbtraderumors.com. Fox Sports Engage Network. Retrieved January 6, 2019.
- Rosenthal, Ken (February 22, 2016). "How A.J. Hinch went from bust to among the best as a manager". Foxsports.com. Fox Sports. Retrieved January 6, 2019.
- Center, Bill (October 26, 2011). "Byrnes officially becomes Padres GM as Hoyer, McLeod join Cubs". Sandiegouniontribune.com. San Diego Union-Tribune. Retrieved January 6, 2019.
- "Dodgers name Farhan Zaidi general manager; Josh Byrnes SVP, baseball operations". Dodgers.com. Los Angeles Dodgers. November 6, 2014. Retrieved 2011-10-27.
- Shelburne, Ramona (April 8, 2015). "Los Angeles Dodgers' front office think tank is a force to be reckoned with". abc7.com. KABC. Retrieved January 6, 2019.