San Jose Police Department Sgt. Heather Randol said detectives searched McDonald's San Jose home.
Randol said an area hospital notified police late Tuesday night that a woman was seeking treatment.
"The victim alleged she was possibly sexually assaulted a day prior," Randol said. "Based on preliminary investigation, detectives secured a search warrant and served it at the alleged suspect's residence in San Jose."
Randol didn't immediately respond to follow-up questions seeking to clarify the reference to the alleged victim saying she was "possibly sexually assaulted."
No arrests have been made, nor have charges been filed.
McDonald could not be immediately reached for comment. Dan Beckler, spokesman for the 49ers, didn't immediately return a phone call.
NFL spokesman Brian McCarthy said the league is looking into the matter.
This is the second time in recent months that McDonald has been the subject of a police investigation.
Last month, the Santa Clara County district attorney's office announced that it declined to file charges against the defensive lineman in a domestic violence investigation stemming from his Aug. 31 arrest.
Prosecutors cited conflicting versions of what happened, a lack of verifiable eyewitnesses and a lack of cooperation by the alleged victim, McDonald's fianceé.
McDonald has played all season despite pressure on the 49ers to bench him.
McDonald said in November that he and his fianceé remain together and are working to strengthen their relationship.
"We love each other," McDonald said at the time.
Information from the Associated Press was used in this report.