Nadal exited the Australian Open with a defeat to Dominic Thiem in the quarter-finals while Djokovic went on to beat the Austrian in the final to claim a record-extending eighth title at Melbourne Park.
Nadal will have the chance to claim the top spot back on Monday if he wins his third title in Acapulco and Djokovic fails to reach the semi-finals of the Dubai Tennis Championships.
However, Nadal's path to victory is anything but easy with a host of top names taking part including champion Nick Kyrgios, Melbourne semi-finalist Alexander Zverev, multiple major winner Stan Wawrinka and high-flying Canadian Felix Auger-Aliassime.
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"It's a very tough tournament. It's one of the best tournaments of the world, one of the most beautiful tournaments of the world," said Nadal, who begins his campaign against countryman Pablo Andujar.
"That attracts the best players, so it's always a very tough draw here. But that's nice and that's very positive for the tournament."
Nadal won the title at Acapulco in 2005 and then again in 2013, after which it switched playing surface to hardcourts from clay.
Explaining why he feels in the comfort zone in Acapulco, Nadal told the ATP Tour: "(I speak the) same language. Nice people, always very friendly people. Every time that I am here I feel a little bit like home".
Nadal lost to Kyrgios last year and later accused the mercurial Australian of lacking respect after he employed an underarm serve during the contest.
Nadal has won the title or reached the final in three of his four appearances and views his 2013 win as a "key moment" in his career.
"This event was the biggest one until that moment that I won (in 2005). After that I started to achieve a lot of important things," Nadal said. "It was like the beginning of something special.
"When I won here in 2013 it was probably a key moment in my career because I came back after very long knee injury. I won in Sao Paulo, but with a lot of problems, without playing very well. But I came here and I played great again.
"Winning here made me feel confident again ... so 2013 was even more special than 2005."
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