Ole Gunnar Solskjaer’s side were set to travel to Reale Arena, in San Sebastian, Spain, to take on the Basque club on Thursday 18 February.
However, the game, which kicks off at 17:55 GMT, has been moved to Italy because of Spanish government restrictions on travellers entering the country from England, due to the new COVID-19 variant.
The second leg, to be played at Old Trafford at 20:00 GMT on Thursday 25 February, remains unchanged.
Both games against La Real, who boast ex-Reds winger Adnan Januzaj and former Manchester City midfielder David Silva in their ranks, will take place behind closed doors.