Both sides bagged vital victories in the Premier League last weekend, with the Magpies enjoying a 1-0 win against Leicester City while Saints were 3-1 winners against Wolves at St Mary's.
Those results, along with Brighton failing to beat Cardiff on Tuesday, means top-flight safety appears to be all but assured for these two teams.
Before being beaten by Crystal Palace earlier this month, Newcastle had won five successive home matches in the Premier League. William Hill offer 7/5 (2.40) that Rafa Benitez's men take all three points on Tyneside.
Southampton have been beaten in just two of their last seven away Premier League matches and William Hill go 11/5 (3.20) that the Saints come out on top. It is 21/10 (3.10) that Saturday's showdown ends in stalemate.
Florian Lejeune will not feature for the Magpies again this season. The French defender faces surgery after suffering knee ligament damage. Sean Longstaff, too, is expected to miss Newcastle's final four fixtures through injury.
Mario Lemina and Michael Obafemi are sidelined for Saints. Both men are set to sit out the remainder of the campaign.
These two teams played out a drab goalless drawing when they met at St Mary's in October. However, it is worth noting that before that, this fixture produced at least three goals in seven successive renewals.
Benitez's team were impressive in their victory at King Power Stadium last time out but more regularly produce their best in front of their fervent home support, where seven of their 10 Premier League wins this season have come.
Furthermore, the Magpies have lost just one of their last 14 home fixtures against Southampton - an impressive record that will surely fill the hosts with confidence ahead of this clash.
With the threat of relegation all but extinguished, Benitez's team could turn on the style. As such, value could lie in backing the Magpies at 7/5 (2.40) to make it six wins from seven on home turf when Southampton visit St James' Park.