Perez made the switch to St James' Park in 2014 from Tenerife but he is yet to taste success at St Mary's, losing 4-0 in the same year he arrived before ending up on the wrong side of a 3-1 scoreline in 2016.
The former Spain Under-21 international has been an ever-present for Newcastle in the Premier League season but, despite the numerous opportunities, he is yet to open his account.
Rafael Benitez's men ground out a hard-fought 1-1 draw at home to Liverpool last time out and the players have been working hard during the international break to be ready for the south coast trip.
The Magpies have not won at Southampton since 2013 but Perez, who is targeting a spot in La Roja's squad for the 2018 World Cup, is confident his side can return to the north east with all three points.
"It feels strange – I haven't won in that stadium. But this can be a good game to break that and get the three points," he told nufc.co.uk. "It's been a great month before the international break. It helps, this kind of break sometimes, to rest and to come back as fit as possible.
"As soon as you're back in Newcastle you start thinking about your job and the work you have to do, and trying to get ready for the challenge. Sometimes to be able to see the family, spend some time at your natural home, it makes you feel better and able to come back happy and ready for whatever is coming up."