Lopez dominated the last climb of an action-packed day to claim a solo victory ahead of Ilnur Zakarin (Katusha-Alpecin) and Wilco Kelderman (Sunweb).
Froome came fifth in stage 15's mountain finish in the Sierra Nevada after a triple whammy of climbs, 47 seconds behind Lopez, crossing the finish six seconds ahead of Nibali, who finished seventh.
The stage, which finished at the Sierra Nevada ski station, featured two first category and one 'above category' climbs in the final 70km.
The Sierra Nevada is commonly used by riders for altitude training, which added another layer of difficulty to the stage, and Froome had said he had been saving himself in Saturday's climb up La Pandera for Sunday's gruelling circuit.
Froome had awful memories of last year's Vuelta stage 15, when Alberto Contador (Trek-Segafredo) and eventual winner Nairo Quintana (Movistar) attacked from the starting gun, leaving the now four-time Tour de France winner isolated from his team and wrecking his bid to win the overall race.
Sky were determined not to make the same mistakes again and on Sunday kept a tight check on Nibali's movements.
Nibali, who did not compete in this year's Tour, waited his turn to attack while Alberto Contador, Romain Bardet (AG2R) and Lopez formed a group ahead of Froome's bunch.
TheBahrain-Merida rider finally made his move with 13km to go and opened up a 20-second gap with Froome's group but could not sustain the pressure and was soon caught.
Monday is the second rest day of the race, which continues on Tuesday with an individual time trial, where Froome will be looking to strike another blow in his bid to become the first rider in 39 years to win the Tour de France and La Vuelta in the same season.
