Nadal downs battling Nishikori to reach Barcelona quarter-finals
The world number three triumphed 6-0, 2-6, 6-2 over 2014 and 2015 champion Nishikori and next face Britain's Cameron Norrie, a fellow left-hander, for a place in the semi-finals.
Nadal, who suffered a surprise quarter-final exit at the Monte Carlo Masters last week, had also required three sets to beat Belarusian qualifier Ilya Ivashka, ranked at 111, in his Barcelona opener on Wednesday.
World number 58 Norrie progressed when Belgian eighth seed David Goffin retired with an injury in the second set.
Nadal defeated Norrie in their only previous meeting in straight sets in the Australian Open third round in February.
Second seed Stefanos Tsitsipas, the champion in Monte Carlo, eased into the last-eight with a 7-5, 6-3 victory Australian 14th seed Alex de Minaur.
Tsitsipas next faces 11th seeded Canadian Felix Auger-Aliassime who got the better of compatriot Denis Shapovalov 6-2, 6-3.
"I was happy with my level today," said Auger-Aliassime.
"It's never easy to play against him and it's great to have won in straight sets. The next match won't be easy, a tough challenge."
Russian third seed Andrey Rublev, the runner-up to Tsitsipas in Monte Carlo, claimed a 6-4, 6-7 (4/7), 6-4 victory over Spain's Albert Ramos-Vinolas in two and a half hours.
Rublev, who has a tour-leading 26 wins in 2021, fired 35 winners past the Spanish clay-courter.
He has an intriguing quarter-final against red-hot Italian teenager and 11th seed Jannik Sinner who defeated fifth seed Roberto Bautista Agut 7-6 (11/9), 6-2.
It was Sinner's third win over the veteran Spaniard this year.