Defending champion Atletico Madrid has the most challenging matchup, playing at Rayo Vallecano, while the two traditional powerhouses start the competition at home.
The new season features a number of high-profile signings for the top clubs and several coaching debuts.
Here are five things to know about the first round of the Spanish league, which kicks off with Athletic Bilbao at Malaga on Saturday:
Barcelona can't wait to put this summer behind it and start playing football.
This week, Barcelona lost its appeal against FIFA's one-year transfer ban for violating rules regarding the signing of youth players. It also had the delicate task of presenting Luis Suarez after it signed the hot-headed Uruguay forward despite his latest suspension for biting an opponent, which will sideline him until Oct. 25.
Now the club is eager to erase last season's failure to win a major trophy for the first time in seven years.
Barcelona hosts Elche on Sunday at Camp Nou. It will be the debut of several other new players, like Ivan Rakitic, and coach Luis Enrique, a former player brought back to get the most out of a highly talented squad that fell short last campaign.
"When you start a season your hope is renewed," said Barcelona defender Javier Mascherano. "Our obligation is to fight for all the titles we can."
Two years ago Eibar was playing in Spain's third division.
Now, after a spectacular rise inspired by coach Gaizka Garitano, the tiny club is set to play its first game in the top flight in its 74-year-old history.
Eibar hosts Real Sociedad in a Basque Country derby on Sunday at its Ipurua Stadium, which has a capacity of just 5,200 spectators.
"It will be a new experience for everyone," said Eibar goalkeeper Xabier Irureta. "We want the day to finally get here when we play Real (Sociedad). There will be a lot of partying."
Real Madrid and Atletico Madrid will not player their respective matches until Monday in order to give them an extra day of rest after they play the second leg of the Spanish Super Cup on Friday.
Madrid has only won the league once in the last six seasons and launches its bid to change that against promoted club Cordoba.
New arrivals James Rodriguez and Toni Kroos could get their Spanish league debuts. Rodriguez scored in his first official game at the Santiago Bernabeu Stadium on Tuesday in the first leg of the Super Cup, which the teams drew 1-1.
Cordoba is coached by former Barcelona and Chelsea player Albert Ferrer.
With all the hype generated by the transfer activity at Barcelona and Real Madrid this offseason, it's easy to forget that Atletico is still the team to dethrone in La Liga.
Diego Simeone's team opens its title defense at crosstown rival Rayo Vallecano on Monday night.
BRING IN THE COACHES
Eight coaches will make their debut for their new teams this weekend.
The toughest introduction will likely be for Valencia's new manager, Portuguese Nuno Espirito Santo, who has to take his team to Europa League champion Sevilla.
Other managers to debut are Sergio Gonzalez for Espanyol, Joaquin Caparros for Granada, Jose Mendilibar for Levante, Javi Gracia for Malaga, Eduardo Berizzo for Celta Vigo and Victor Fernandez for the promoted Deportivo La Coruna.