Barcelona remain unbeaten in La Liga after 23 games, extending their longest run without losing from the start of a campaign.
Messi was pivotal in Barcelona's 1-0 win where he created something out of nothing for Luis Suarez to head home in the 67th minute.
Philippe Coutinho was named on the bench for the first time since his 160 million-euro ($192 million) transfer from Liverpool earlier this month.
Lionel Messi broke the deadlock from a Jordi Alba assist.
Real Madrid remain down in fourth place, but do have a game in hand on their rivals.
Troubled Barcelona were dealt a new blow ahead of the start of the Spanish league season when Luis Suarez was ruled out for a month with a knee injury on Thursday.
Victory continues Real Madrid's run of success under Zinedine Zidane with the European champions now having lifted seven trophies in the 20 months since the Frenchman took charge.
Barcelona football star Lionel Messi, who is enjoying his honeymoon in the Caribbean with wife Antonella and two sons, was joined by club teammate Luis Suarez and his family.
Argentine media called it the "wedding of the century" for Rosario, the gritty northern port city where Lionel Messi, 30, and his bride, 29, met when the player was nine years old.
Luis Suarez and other football stars were watched by curious locals as they stepped off private jets on Thursday at Rosario's airport.
The luxurious City Center casino-hotel complex in Rosario, where guests will stay and the ceremony is expected to take place, borders a poor neighborhood known as the birthplace of the bloody drug gang Los Monos.
Barcelona and Real Madrid remain locked together on 81 points at the top of La Liga after seeing off Espanyol and Valencia respectively on Saturday.
Sergi Roberto capped the biggest comeback in Champions League history when he stretched to turn home Neymar's dinked cross to the delight of a near 100,000 at a rocking Camp Nou, making the score 6-5 on aggregate in FC Barcelona's favour.
Barcelona defeated Atletico Madrid 2-1 to go top of the La Liga standings on Sunday.
Luis Suarez was one of three players sent-off in a pulsating second-half and will miss May's final against Alaves or Celta Vigo.
Luis Suarez and Lionel Messi scored a goal each to give Barcelona the lead in the first leg semi-final of Copa del Rey on Wednesday.
Sevilla are just a point behind Real Madrid, who have a game in hand, while defending champions Barcelona are a point further adrift in the La Liga standings
Athletic Bilbao played a man down from the 74th minute, and two men down from the 80th because of red cards in a drama-filled first-leg match against Barcelona in the Copa del Rey round of 16