The 27-year-old world number two, who has not played for Spain since their 2011 Davis Cup triumph against Argentina, will play on his favourite clay surface in the tie at Madrid's Caja Magica.
Nadal will face Sergiy Stakhovskiy in the second singles rubber on Friday, after Fernando Verdasco and Alexandr Dolgopolov meet in the first match.
Elsewhere, Andy Murray will make his Davis Cup return for Great Britain in their tie against Croatia.
The Wimbledon champion will face Borna Coric in the first singles rubber on Friday in Umag.
Roger Federer will not feature for Switzerland in their tie against Ecuador, but world number 10 Stanislas Wawrinka, a semi-finalist at the US Open last week, will feature for the Swiss.
Meanwhile, Philipp Kohlschreiber will play the opening rubber for hosts Germany in Friday's Davis Cup World Group play-off against Brazil's Rogerio Dutra Silva, ranked 102 places below the German.
The 29-year-old Kohlschreiber, 25th in the world, takes on the 127th-ranked Brazilian indoors on hard court in Ulm, south-west Germany, with Florian Mayer playing Thomaz Bellucci in Friday's second singles rubber.
And Poland will be without their leading player, 14th-ranked Jerzy Janowicz when they face an Australia team led by Lleyton Hewitt in Warsaw.
Davis Cup World Group play-offs this weekend:
Spain v Ukraine
At Groningen, Netherlands
Netherlands v Austria
At Umag, Croatia
Croatia v Great Britain
At Neuchatel, Switzerland
Switzerland v Ecuador
At Neu-Ulm, Germany
Germany v Brazil
Poland v Australia
At Antwerp, Belgium
Belgium v Israel
Japan v Colombia