The Catalan giants responded to wins from Real Madrid and Atletico Madrid earlier in the day, with their four goals making it 180 in 2015 - the most ever managed by a Spanish club in a calendar year.
The opening goal arrived shortly before the half-hour mark when Adan was harshly penalised for clattering into Messi while coming to claim a cross, and the hosts were given another helping hand as Heiko Westermann got the final touch to put the rebound into his own net after Neymar had slipped and hit the crossbar from the initial penalty.
Betis boss Pepe Mel was sent to the stands for his protests against the penalty, and things got even worse for his side when Barca doubled their advantage less than five minutes later.
It was Messi's turn to adorn his landmark appearance with a goal, lending the ball to Neymar before getting in the box and applying a simple finish to the Brazilian's return pass.
It should have been three before the half was out too, but Luis Suarez could not squeeze the ball in from a tight angle having been played clean through on goal and rounding the Betis keeper.
Suarez did get his name on the scoresheet in the opening minutes of the second half, however, rolling a finish into the bottom corner after Sergio Busquets had won the ball on the edge of the Betis box.
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The chances continued to arrive for Barca, and they came within inches of adding to their lead when Neymar hit the post before Messi saw an effort saved by Adan seconds later.
The woodwork came to the visitors' rescue on three more occasions during a five-minute spell as Messi twice struck the crossbar with free kicks and Alves saw an attempted chip beat the keeper but come back off the frame of the goal.
Barca's fourth arrived shortly after that, and it was a second for Suarez as he combined with Neymar before finishing from close range to well and truly put the game to bed.
The result means that the Catalan giants will end 2015 top of the table, while Betis are now winless in five in all competitions.