Upshaw was an active member of the bargaining committee for the National Football League Players' Association (NFLPA) throughout the late 1970s and early 1980s. He led the NFLPA in its unsuccessful strike in 1987 and through years of anti-trust litigation against the league, including a brief period in which the NFLPA became a professional association rather than a union, that ended with the union's acceptance of a salary cap in return for free agency and an enhanced share of league revenues for the union's members. Until his death, he was the Executive Director of the Association.
He alienated many retired players after comments he made in response to 325 former AFL and NFL players receiving minimal retirement benefits. When the former players attempted to have the league and the Association consider their plight, Upshaw responded: "The bottom line is I don't work for them. They don't hire me and they can't fire me. They can complain about me all day long. They can have their opinion. But the active players have the vote." Upshaw later said he was misquoted and was speaking solely about fellow Hall of Famer Joe DeLamielleure, further saying "A guy like DeLamielleure says the things he said about me; you think I'm going to invite him to dinner? No. I'm going to break his damn neck." While Upshaw's comments were true on the letter of the NFL's benefit rules—the NFLPA is charged with the union rights of active players, and any matters dealing with retirees are subject to negotiations between the NFLPA and the NFL Management Council—they were badly received by both former and current players, fans, and the media. Prior to his death, a campaign was allegedly being led by Ravens kicker Matt Stover to oust Gene Upshaw as head of the NFLPA; however, all parties have denied such a plan. Stover along with a number of other players claim to have only been seeking a definite succession plan in order to avoid a drawn out and messy transfer of power such as Upshaw's death has seen realized. Tennessee Titans center Kevin Mawae, president of the NFLPA, had denied reports of mass callings from players for Upshaw to step down.
In 2004, the NCAA Division II sports information directors awarded the first Gene Upshaw Division II Lineman of the Year award. It is presented each year during the weekend of the NCAA Division II Football Championship by the Manheim (Pennsylvania) Touchdown Club.
In mid-August 2008 at his home in Lake Tahoe, Upshaw began to feel ill. His wife Terri noticed that his breathing was labored, so she convinced him to go to the emergency room, where he was diagnosed with pancreatic cancer on August 17. On August 20, Upshaw died with Terri and his sons Eugene III, Justin, and Daniel by his side, five days after his 63rd birthday.
After his sudden death, the NFL announced that for the opening weekend of the 2008 season, all 32 teams would wear a patch on the left chest of the jerseys with the initials "GU" and the number 63, Upshaw's jersey number with the Oakland Raiders; the patch was also painted onto every NFL field for Week 1. Beginning in the second week of the season, all teams wore the patch as a decal on their backs of their helmets instead of a shoulder patch; the Raiders continued to wear the patch on their shoulder throughout the season.
Gene’s wife, Terri, and sons Justin and Daniel, established the Gene Upshaw Memorial Fund in memory of Gene. In recognition of the extraordinary care he received at Tahoe Forest Hospital, The Gene Upshaw Memorial Fund has created a partnership with Tahoe Forest Health System to provide funding for important health programs and research.  The mission of the Gene Upshaw Memorial Fund is to honor Gene Upshaw’s legacy and advance the Upshaw family’s passion for quality medical treatment, care for patients and their families,  sustainability and advancement of medical technology, and funding for research in areas such as traumatic brain injury (TBI). The Gene Upshaw Memorial Fund is currently partnered with Tahoe Forest Health System,  the Gene Upshaw Memorial Tahoe Forest Cancer Center, and the Tahoe Institute for Rural Health Research (TIRHR) to advance its mission.