With a win over Malaga on Saturday, Barcelona can rob Real Madrid of their sole claim to the best single season in the history of the Spanish league.
Madrid set a record of reaching the 100-point mark en route to winning the title last season. And with 97 points heading into the final round, Barcelona can equal that milestone with a victory at Camp Nou.
Also, Jose Mourinho will coach his last game for Madrid during Saturday's full slate of games when Osasuna visits. Neither team are playing for anything beyond pride.
Mourinho has avoided speaking to the media since club president Florentino Perez announced he was leaving Madrid following the team's loss to Atletico Madrid in the final of the Copa del Rey, leaving them without a major trophy this season.
Valencia and Real Sociedad face decisive games to see who finishes in fourth place and will join the Champions League next season, while only one of the four bottom teams will avoid relegation.
Barcelona will be without Lionel Messi, sidelined with a nagging hamstring injury, giving its other forwards one last chance to prove their worth before the arrival of Brazil sensation Neymar, who will be presented on Monday.
Forward Alexis Sanchez has said he will stay at the club after his improved performances during recent months, but the future of Spain international David Villa is murkier with Neymar set to replace him on the left flank.
The match will be Manuel Pellegrini's last for Malaga. The Chilean is set to take over Premier League side Manchester City.
Malaga are trying to secure a Europa League spot with the hope that the Court of Arbitration for Sport will overturn UEFA's one-year ban of the club from European competition for not paying wages and taxes on time.
Champions league fight
After Madrid and Barcelona start the final round, the other eight games will be played simultaneously since most could have implications for either European competition or relegation.
Valencia are two points ahead of Sociedad in fourth place before they travel to Sevilla, while Sociedad visit a Deportivo La Coruna side clinging to safety by one point and in need of a win to assure they do not fall into the second division for the second time in three years.
If Valencia and Sociedad end the season level on points, Sociedad holds the head-to-head tiebreaker.
Valencia are going to have a tough time (at Sevilla). The chance to play in the Champions League is very exciting
"If we win, we have options," Sociedad striker Imanol Agirretxe said.
"Valencia are going to have a tough time (at Sevilla). The chance to play in the Champions League is very exciting. You only get this type of chance a few times in your life, and we don't want to let it slip away."
With either Valencia or Sociedad finishing in fifth and heading to the Europa League as a consolation prize, the other two - and likely three due to Malaga's ban - Europa League berths are still up for grabs.
Malaga enter the round in sixth place, with Real Betis two points behind before they visit Levante.
Rayo Vallecano have eighth place locked up and would qualify for the Europa League in place of Malaga if their ban is upheld.
They can also pass Betis for seventh place and earn their berth outright if Betis lose and Rayo beat an Athletic Bilbao team with nothing at stake. Granada hostsGetafe, also with neither playing for anything.
At the bottom, Deportivo have 35 points, while Celta Vigo and Real Zaragoza each have 34 and Mallorca is last with 33. The bottom three will go down.
The three teams currently in the drop zone all play at home and against opponents with nothing to play for. Celta host Espanyol, Zaragoza face third-place Atletico, and Mallorca welcome Valladolid.
"We still have one last shot and we have to make the most of it," Zaragoza goalkeeper Roberto Jimenez said.
"There's no use in looking back. We have to recover our hope and give one last push to end the season."