The Magpies may have faced the likes of Liverpool, Manchester City and Manchester United already this term, but Bruce feels that this weekend's clash at home to Ralph Hasenhüttl's side could be seismic for his team as they look to climb into the top ten.
Thursday night's win at Sheffield United saw Newcastle move up to 11th, and Bruce knows that the visit of the Saints - followed by fixtures against Burnley and Crystal Palace before Christmas - could help to shape the season.
He said: "We've got a big game. It's arguably the biggest now.
"Southampton have won back to back games (but) we've got a good opportunity. We've got three teams in and around us, four of our next six games are at home; at St. James' we've done very well, so it gives us a wonderful opportunity - but that's all it is."
Although they sit just one place outside the bottom three, since losing 9-0 to Leicester in October Hasenhüttl's men have responded well - just like the Magpies following their own heavy defeat to the Foxes in September.
"They drew with Arsenal and they've won back to back games at home, so we've got them just when they're finding a bit of form," said Bruce.
"When I look through their squad, what they've got up front and what they've got in midfield, they've got good players so it's a hard challenge again."
Bruce revealed that Allan Saint-Maximin has been nursing an ankle injury, which could make him a doubt for Sunday's game, while he must make a decision on whether Andy Carroll can start two games in four days.
"I haven't even decided that just yet," the head coach insisted. "We'll come to Sunday and see how he is. We'll see how he recovers, see how he is on Saturday.
"That might be asking too much, but I'll see how he is."