Uys and van der Heijden will both miss the game at Kingston Park due to injury. The former is suffering from a groin problem picked up during the Boxing Day clash against Sale, while van der Heijden has a slight knee ligament strain.
Jeremy Manning comes in on the wing, with Luke Eves moving into midfield in place of Uys. Adriaan Fondse, meanwhile, is promoted to the starting XV for the first time since his move in November.
"We have got to turn things around against one of the best teams in the country, but the boys know they have got what it takes," head coach Alan Tait told the official Falcons website.
"It has been a real battle to get anything on the road so we have to make Kingston Park a fortress. It is a very quick turnaround against a team who will be playing a couple of notches up from what we played against at Sale.
"We will certainly have our work cut out but it is at Kingston Park and we do play well there."
Meanwhile, Northampton number eight Roger Wilson will make his hundredth appearance for Saints.
The 30-year-old Irish international joined the Saints in the summer of 2008. In addition to his 99 appearances, he has picked up winners' medals in the European Challenge Cup and LV= Cup as well as his runners-up medal in the 2011 Heineken Cup.
Director of rugby Jim Mallinder says that Wilson has been an important player for the Saints since his arrival at Franklin's Gardens.
"Roger is a quality player who has a positive influence on a game," said the Saints boss.
"He has formed good partnerships with all of the other back row players and scrum-halves we have in our squad, and deserves the accolades that will come with his hundredth appearance."
Turning his attention to the game itself, Mallinder said that the Falcons should not be underestimated whatsoever.
"Kingston Park is one of the toughest places for opposition teams to play in Aviva Premiership Rugby," he commented.
"Newcastle have shown that by winning their last six matches at home. They've changed their squad a little bit since they played at Franklin's Gardens and brought in some players who have had a big impact. We will have to be right on top of our game on Saturday if we are to get the positive result we want."
Samu Manoa replaces flanker Tom Wood in the starting line-up after the 22-13 home win over Bath last time out on Christmas Eve.
Christian Day and Brian Mujati both make the replacements bench, with Tom Mercey dropping out.
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