Darnold was hit by defensive lineman C.J. Brewer as he was throwing the ball away. His left ankle appeared to become twisted as he landed awkwardly on the turf.
He is believed to have suffered a high-ankle sprain based on initial evaluation, according to sources. He will have an MRI on Saturday to determine the severity and if there is other damage.
Darnold was five-of-11 for 49 yards and ran for a one-yard touchdown before exiting.
If Darnold is out for any length of time, P.J. Walker would likely move into a backup role behind Mayfield. Rookie quarterback Matt Corral suffered a season-ending injury when he tore a ligament in his foot in a 20-10 loss to the New England Patriots last week.