Nadal, however, won again.
Returning from injury issues of his own, Klizan broke three times-converting each of his three break-point chances-even though Djokovic served at 79 percent.
10 David Goffin survived a scare against Spaniard Marcel Granollers, after fighting back from 5-1 down in the second set, to win his second round tie 4-6, 7-6 (2), 6-2.
Djokovic's disappointing 2018 continued in a 6-2 1-6 6-3 loss to Martin Klizan, the 12-time major victor having been a late addition to the draw following a round-three loss to Thiem in Monte Carlo.
As for Klizan, he progresses to face Feliciano Lopez in the third round in Barcelona.
Nadal has not dropped a set since losing to Dominic Thiem in Rome last season - a loss that ended a run of 17 straight victories - and it's tough to see him losing one anytime soon, with no player amassing more than four games in a set during this run.
Nadal, however, needs to win the title in Barcelona in order to remain at the top spot in the ATP Rankings, or else Swiss tennis maestro ad his long-time rival Roger Federer will take over.
Another break followed in the opening game of the second set, but any thoughts of Nadal racing through for a quick finish were put to bed as Carballes Baena continued to keep him honest, breaking back in game six for 3-3 as Nadal drilled a forehand long.
The Serb's form since the Australian Open has been horrendous, with first-round exits at both Indian Wells and the Miami Open in March.
Having received a first-round bye, Nishikori lost his second-round match to Spain's Guillermo Garcia-Lopez 6-3, 0-0 when he retired after the first set.