Smith-Schuster exited with a concussion after taking a helmet-to-helmet hit from Greedy Williams. He lay on the ground for several moments before being helped up and escorted off the field and into the locker room during the second quarter.
Conner aggravated a shoulder injury that forced him to miss Weeks 9 and 10. He lasted five carries against the Browns before re-injuring himself.
No penalty was called on Williams' hit on Smith-Schuster, but a flag was thrown against Cleveland on the same play for roughing the passer after a rusher went helmet-to-helmet on quarterback Mason Rudolph.
Smith-Schuster and Conner were both ruled out before halftime.
Smith-Schuster came into Week 11 with 36 receptions for 503 yards and three touchdowns on the year. Conner entered with 380 yards and four touchdowns on 97 carries for the season.
Both third-year players were Pro Bowlers in 2018.