The Saints arrive on Tyneside sitting rock bottom of the Premier League and six points from safety, with their cause not helped by a home defeat to Bournemouth in midweek.
United, though, go into the game in fine form, having netted ten goals already in a week which has seen them beat Tottenham Hotspur 6-1 and Everton 4-1 respectively.
Howe is keen to avoid any complacency, however, as his side go in search of a victory which would take them another step closer to securing a European berth next term.
The Magpies head coach spoke to media following Thursday's win at Goodison Park. Here are some of the key points up for discussion - including his thoughts on comparisons between Newcastle's Alexander Isak and the great Thierry Henry:
On the upcoming visit of Ruben Selles' men this weekend...
"It's a difficult game. I think they are fighting. I watched the Arsenal game very recently - they were very good against the league leaders, they scored three goals and looked a real threat in transitions and set plays.
"We've played Southampton three times I think this season so we know their qualities. They're a good team. It's going to be difficult."
On the growing feeling of positivity and unity at the club during their fine recent run...
"Winning is everything. It's what you're paid to do, but it's what you plan to do. And I'm so proud of everyone connected with the club this year with what we've given - players, staff, board, everyone - and we feel really united at the moment.
"Things are going well and we're not taking that for granted because we know quickly it can change, but we're enjoying the feeling we're having and long may that continue."
On comparisons between Alexander Isak and Thierry Henry, following his stunning run of form and magnificent assist at Everton...
"I can see the comparisons there. I think everyone is different - there's no two players that are the same - but I do think he has some of the characteristics that Thierry had. He's got the speed and a similar build and frame. The footwork for the assist tonight was was truly remarkable, really, and I think he's got a lot of potential to improve and get better so it's been a great, great start for him here."
On Allan Saint-Maximin's ongoing recovery from injury...
"He won't be available for Sunday - maybe the game after, but no guarantee at this moment.
"I certainly hope he'll be before the end of the season but with hamstring injuries there's always that element of doubt. He's not had a setback - he just needs to build his fitness levels up and make sure he's fully fit before he comes back."
On the confidence surging through his squad on their current run of seven wins in their last eight games...
"I think there's a real confidence about the group of players we have - regardless of who we pick at the moment, it seems that confidence is there in the group. I thought we saw it with Anthony (Gordon) and Elliot (Anderson) when they came on as well.
"I think conference is such a key thing in any football club and any team so I think the key thing for us is not to take that for granted, and not to back off from what we're doing to create that and what the players are doing to create that. There's a lot of hard work going in and we need to not take our eye off the ball."