Halftime substitute Raphinha cancelled out Valladolid's first-half opener in the 54th minute on Saturday (Sunday AEST).
Lopez continued his quietly superb season by bagging the winner six minutes later for a 2-1 road victory.
Hansi Flick played with fire by rotating his starting XI ahead of Tuesday's trip to Milan, where Barcelona and Inter will see who can tip the balance in their semi-final after delivering a 3-3 thriller last week in Spain.
"I am happy that we won the three points, but I am also happy that some players had less minutes before the important match against Inter on Tuesday," Flick said.
Valladolid made a surprising start when Ivan Sanchez's shot deflected off Ronald Araujo, hit the turf and looped over goalkeeper Marc-Andre ter Stegen, who was making his first start since recovering from a right knee injury in September.
Barcelona were stalled until Lamine Yamal replaced injured debutant Daniel Rodriguez, whose first game ended after just over half an hour when he hurt his right arm.
Raphinha replaced an ineffective Ansu Fati at halftime. The Brazil forward, who has come through in the clutch for Barcelona this season, drilled in a loose ball after goalie Andre Ferreira punched a cross by Yamal to the edge of the area. Fermin followed up moments later with a precise, low strike into the corner.
Yamal had a goal-bound shot saved on the line by Valladolid's Antonio Candela in the 80th minute. The 17-year-old also delivered the dribble of the match, when he spun with the ball to twirl past two defenders.
Barcelona opened a seven-point gap over Real Madrid, who they beat last weekend in the Copa del Rey final to launch their bid for a treble.
Madrid host Celta Vigo on Sunday (Monday AEST). After this round there will be four games left, including a "clasico" in Barcelona next weekend.
"I was really eager to play and enjoy being on the field. And there is no better way to return than with a win," ter Stegen said on his first appearance in seven months. "We are keeping up the momentum ahead of some spectacular games."
Valladolid were relegated last week after winning just four of 33 games.
Valladolid's disgruntled fans protested against club owner, Brazil and Real Madrid great Ronaldo, before and during the Barcelona game. Supporters waved fliers that looked like 500-euro notes with the face of Ronaldo and the message in English "Ronaldo go home" on them, before tossing them toward the turf.
In other action, third-placed Atletico Madrid drew 0-0 at Alaves.
Ayoze Perez's double led Villarreal to a 4-2 win over Osasuna and reinforced their hold on fifth place, which next season will earn a Champions League berth. Real Betis, in sixth, were four points behind with a game in hand.
Hugo Duro scored twice for Valencia as they won 3-2 at Las Palmas and kept the Canary Islands club in the relegation zone.
