Joe Gomez was withdrawn at half-time of Liverpool's trip to Southampton with a suspected ankle injury.
The defender was hurt when Mohammed Salisu landed awkwardly on him in first-half stoppage-time at St Mary's with the scores level at 1-1.
Gomez was taken to the sidelines but Liverpool boss Jurgen Klopp refused to make the change initially, preferring to give his player the benefit of some treatment during the interval to see how he responded.
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However, the former Charlton Athletic youngster was unable to continue and he was replaced for the second period by captain Jordan Henderson as James Milner went to right-back. Trent Alexander-Arnold, the Reds' usual right-back, was left out of the squad entirely after his performance in the FA Cup final on Saturday.
The injury will be a bitterly disappointing one for Gomez having only made four Premier League starts this season - all at right-back - following a long-term issue picked up on England duty in November 2020.
That knee issue required surgery and left the 24-year-old sidelined for nine months of competitive action. Gomez has also previously endured four serious and long-term lay-offs through injury during his time on Merseyside.
Liverpool went on to win 2-1 thanks to a second-half header from Joel Matip.
Klopp will deliver an early update on Gomez in his post-match press conference.
