Hand came down awkwardly on her left knee late in the first half against North Texas.
Hand clenched the knee as she tumbled to the floor.
If the injury is as serious as it looks, Oklahoma will be down to eight healthy players on its roster.
Freshman guard Maddie Manning tore the ACL in her right knee last week and will miss the rest of the season.
Reserves Jacqueline Jeffcoat and Katherine Zander each transferred last March; veteran Lyndsey Cloman chose to end her career because of a lingering back injury in early November; and sophomore Kaylon Williams, who averaged 4.8 points and 5.2 rebounds a year ago, ruptured her Achilles tendon and will miss this entire season.
Hand tore the ACL in her right knee as a sophomore early in the 2009-10 season.
Even after her rehab was complete, she had to sit out several months of the next season, too, after doctors discovered cartilage damage in the knee.