The 20-year-old appeared visibly upset as he left the field after the match on crutches, with an ice pack on his right knee.
Bulldogs coach Brendan McCartney said Smith would be sent for scans on Monday, but the early prognosis was not good.
"They're thinking that it's the big one, an ACL," McCartney said.
"But he's a beauty; he hurt himself trying to stop his man from getting the ball.
"We've just got to get him a good rehab now and get him back into it.
"He's an incredibly strong person, so he'll bounce back."
Smith is in his second year at the Bulldogs after being drafted with pick No.17 in the 2011 NAB AFL Draft.
The tough onballer had been a valuable contributor for his team up until he suffered his injury during the fourth quarter, gathering 18 disposals and laying five tackles.
