The pilots, who weren't immediately identified, ejected around 9:05 a.m., shortly after taking off from Beale Air Force Base on a training mission in a rural part of the state, the service confirmed in a statement.
"One pilot is confirmed deceased, while the other sustained injuries," it stated.
In a video sent to KCRA, a local NBC affiliate in Sacramento, parachutes can be seen in the sky while the aircraft, a trainer designated a TU-2S, spins uncontrollably toward the ground. Photos show smoke billowing from the scene and wreckage strewn across the crash site.
The plane, assigned to the 1st Reconnaissance Squadron, part of the 9th Reconnaissance Wing, went down near the Sutter Buttes mountain range, according to the installation.
"Two pilots were on-board and ejected from the aircraft," the base said in a separate statement. "The incident is currently under investigation. Additional details will be provided as they become available."
Lt. Col. Michael Meridith, a spokesman for the service's Air Combat Command, confirmed the incident earlier in the day at the Air Force Association's annual conference outside Washington, D.C. He said he wasn't aware of the condition of the service members but that a search and rescue operation was underway.
The command initially said the pilots had "safely" ejected and were "awaiting recovery with aircraft in isolated area," but later corrected that statement to say it couldn't confirm their condition.
The U-2 Dragon Lady is a Cold War-era surveillance plane based at Beale. The single-engine jet made by Lockheed Martin Corp. flies as high as 70,000 feet, has a range of 7,000 miles and dates to the 1950s.
The Air Force as of this year had 33 of the aircraft in inventory, including five trainers, according to a fact sheet. Trainer models of the aircraft hold two crew members.
The service had planned to retire the aircraft in 2019 and replace it with a high-altitude drone, the RQ-4 Global Hawk, made by Northrop Grumman Corp.
Deadly accidents involving the U-2 aircraft are relatively rare.
A previous fatal mishap occurred in 2005, when Maj. Duane W. Dively, 43, of Sacramento, was killed when the Dragon Lady he was piloting crashed while returning to a base in the United Arab Emirates, according to The Associated Press.