Rafael Benitezs side start the weekend in 16th, just one place and a single point above their opponents, and know that victory could prove invaluable to their cause.
And the Newcastle boss has told his players to approach each of their remaining nine games as cup finals as they attempt to secure their Premier League status.
He said: "Every game is important. This is the most important because it is the next one, but we have to keep going to the end. We will be trying to win, but we will be doing that until the last one. Every game is a final for us now."
Southampton boss Mauricio Pellegrino, who has played for and worked under Benitez, insists his players are well aware they are in a relegation scrap and believes they are up to the task of securing their survival.
He said: "It is difficult to talk to the fans and say we are getting better because since January the team lifted performances, but now we need results. That is the reality.
"As a manager I have to think about what to do. We need results but the consequence is what we do on the pitch."
Newcastle will make a late decision on the fitness of midfielder Jonjo Shelvey, who missed last weekends 2-0 defeat at Liverpool with a knee problem, but is back in training and could be included.
Striker Islam Slimani is still working his way back from a thigh problem, while keeper Rob Elliot (thigh) and Jesus Gamez (ankle) are also out.
Southampton will still be without captain Steven Davis, who has missed the last three games with a hamstring problem and faces at least another week on the sidelines.
Defender Maya Yoshida (knee) and striker Charlie Austin (hamstring) remain on the casualty list.
