“Pity and Terror in Picasso – the Path to Guernica” will open on April 4th and last five months to celebrate the anniversary of the painting itself, as well as its arrival at the museum 25 years ago.
“Close to 150 masterpieces by the artist will be on show, coming from the (museum's) collection and that of more than 30 institutions from around the world,” the Reina Sofia said in a statement.
Works of art from the Picasso Museum and Georges Pompidou Centre in Paris, Tate Modern in London, MoMA in New York or the Beyeler Foundation in Basel will be on display.
“Guernica” is one of the most well-known works by Picasso, who was born in Spain in 1881 and died in France in 1973 aged 91.
He created it as a commission for Spain's struggling Republican government to represent the country at the 1937 World Fair in Paris.
At the time, Spain was waist-deep in a bloody civil war pitting the Republicans against the troops of future dictator General Francisco Franco.
The painting was inspired by the town of Guernica in the Basque Country of northern Spain, which was bombed on April 26, 1937, a spring market day, by German air forces supporting Franco in the war.
Hundreds died in what set a precedent for a new kind of wartime strategy during World War II – the aerial bombing of civilians.
The painting was transferred to Madrid in 1981 from New York's Museum of Modern Art, where it had been deposited on a long-term loan by Picasso until democracy was restored in Spain.
For fear of attack, it was initially housed behind bullet-proof glass and under armed guard at the Prado Museum in Madrid before it was eventually transferred to the nearby Reina Sofia Museum when it opened in 1992.
The Reina Sofia, a vast former hospital, now displays “Guernica” in a purpose-built gallery on its own.