Van Gaal takes his in-form Manchester United side to Stamford Bridge aiming to secure their first victory over the London club in eight matches.
Chelsea manager Mourinho worked under United boss Van Gaal at Barcelona and the duo remain good friends, as they demonstrated with embraces during and after a 1-1 draw at Old Trafford in October.
That will go out of the window when they pit their wits against each other this weekend, with Chelsea knowing a victory will see them move 10 points clear at the top of the table with six games remaining.
Cesc Fabregas scored the only goal of the game two minutes from time last Sunday to ensure Chelsea edged the West London derby against QPR to remain on course for their first Premier League title for five years.
Mourinho's side are unbeaten in 13 games in all competitions and look set to win two trophies in the Portuguese's second season since returning to the club from Real Madrid, having already lifted the League Cup.
With second-placed Arsenal not in Premier League action this weekend due to their FA Cup semi-final against Reading, Chelsea can take an even stronger grip on top spot by seeing off United.
Van Gaal's side also head into the game in ominous form, though, having secured a derby victory last Sunday to extend their winning run to six top-flight games. They can go second with a win against the leaders.
United are on course to return to the UEFA Champions League next season after beating neighbours Manchester City 4-2 at Old Trafford to move four points ahead of their neighbours.
Branislav Ivanovic and Fernando Torres were sent off when United last won at Stamford Bridge back in October 2012.
Juan Mata was an unused Chelsea substitute in their 3-1 home win over United last season and the Spain midfielder makes his first return to his former club this weekend.
Mata has played a key role in United's impressive form of late, scoring a match-winning double at Liverpool and also finding the back of the net against City last weekend to further endear himself to the Old Trafford faithful.
The ex-Valencia man will be out to prove a point to Mourinho and inspire United to a victory that would end Chelsea's unbeaten home record in the Premier League this season.
Robin van Persie scored a stoppage-time equaliser when the two sides met earlier in the season and the Netherlands striker could make his return from an ankle injury on Saturday, while Luke Shaw (hamstring) could also feature.
United have an injury concern over Michael Carrick (calf) after the England midfielder limped out of the derby.
Chelsea will again be without leading scorer Diego Costa (hamstring) and also have a doubt over fellow striker Loic Remy (calf).
