Second-placed Atletico Madrid are too in action on Saturday as they host Espanyol, with red-hot Antoine Griezmann and company out for three points which would continue their La Liga-leading home record so far.
Espanyol are something of a 'bogey' side for Simeone's men however, having won both their most recent La Liga meetings including a 2-0 victory for the Catalans at the Wanda Metropolitano last season.
Third-placed Sevilla will also aim to stay right in the mix at the top when they visit Leganes on Sunday. A tight game is likely as Pablo Machin's side have drawn their last three on the road, while in-form ‘Lega' are now unbeaten in their last six league outings.
The weekend this time begins early on Friday with Girona hosting Getafe at Montilivi in a meeting of two teams who have both had excellent 2018s and will want a result to stay in the top half over the break.
Friday's late game is a Basque derby which sees Real Sociedad host Alaves. The visitors from Vitoria will be looking for a first La Liga win at Anoeta in over a decade.
Saturday will see a resurgent Real Betis aiming for a fourth straight La Liga victory to ensure they spend the winter break in fifth spot, although visitors Eibar will remember their 4-0 victory at the Estadio Benito Villamarin just two years' back.
The late game on Saturday sees new Athletic Club coach Gaizka Garitano look to stretch his unbeaten run to three games. Visitors Real Valladolid travel to San Mames aiming for a win which would be an excellent end to a great last 12 months for the Castilian club.
Sunday's matches starts with Valencia looking to end the year on a high at Mestalla against bottom team Huesca, whose performances have improved in recent weeks.
The final La Liga game of 2018 has Rayo Vallecano aiming for a second straight win at their Estadio de Vallecas, but visitors Levante can go into the winter break having stretched their unbeaten away run to six games.
Real Madrid and Villarreal are not in La Liga action this weekend, with the reigning UEFA Champions League holders in Abu Dhabi defending their FIFA Club World Cup trophy. Their meeting will now be La Liga's first action of 2019, at Villarreal's Estadio de la Ceramica on January 3.