The team had to find a temporary stadium after California’s Santa Clara County, where they are based, banned contact sports for three weeks to prevent virus spread.
Now the 49ers will play the Buffalo Bills next Monday night at State Farm Stadium in Glendale, Arizona, which is normally the home ground of their rivals, the Arizona Cardinals.
The 49ers will then play there again against the Washington Football Team on 13 December.
The team, which has not announced where they will practice, will return to the stadium again on 26 December to play a scheduled game against the Cardinals.
“The Cardinals organization, State Farm Stadium and League officials have been supportive and accommodating as we work through the many logistical issues involved in relocating NFL games," said the 49ers in a statement.
Their move came after their home county introduced new measures to stem the surge in coronavirus cases and hospitalisations.
"The 49ers are, I think, the most nationally obvious example, but there is no family in our community that is untouched by this pandemic,” county counsel James Williams told CNN.
“Our ICU beds are filling up, hospitals are filling up, we are trying to take every possible measure locally to rein that in,” said Williams.
The restrictions will also impact the NHL’s San Jose Sharks, and college teams from Stanford and San Jose State.