"We've got a problem with Lanzini, who took a knock and didn't play in the second game for Argentina (in Spain)," Moyes told reporters on Friday.
"He's got a problem with his knee so we're assessing it. He's done a good bit of running, so we're hoping he's got a chance," the Scottish manager added.
Striker Andy Carroll is on the mend after suffering an ankle injury and Moyes hopes the powerful forward can play a decisive role in the final part of the campaign as 17th-placed West Ham battle to avoid the drop.
Carroll scored twice in the 2-1 win over West Bromwich Albion on Jan. 2 and has not featured in the league since a late substitute appearance two days later in the 1-1 draw with Tottenham Hotspur at Wembley.
"I'm not sure we can get him fit for 90 minutes, but if I can get him fit to play 20-30 minutes in games between now and the end of the season, I think it'll be really good," Moyes said.
The visit of relegation-threatened Southampton marks the first league game at the London Stadium since West Ham's 3-0 defeat by Burnley this month, a match marred by pitch invasions and ugly scenes in the stands.
Moyes, however, has no fears of a repeat of the unrest that led to life bans for a number of supporters.
"I think the atmosphere will be great. It has been great, with the exception of one occasion, since I've been here. I've got no worries about the supporters, who I believe are right behind the team," Moyes said.
(Reporting by Shrivathsa Sridhar in Bengaluru, editing by Ed Osmond)
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