The ecstatic figure of St. John dominates the canvas, while behind him naked souls writhe in a chaotic storm of emotion as they receive white robes of salvation.

It has been suggested that the Opening of the Fifth Seal served as an inspiration for the early Cubist works of Pablo Picasso, especially Les Demoiselles d'Avignon, which mirrors the expressionistic angularity of the painting.

When Picasso was working on Les Demoiselles d'Avignon, he visited his friend Zuloaga in his studio in Paris and studied El Greco's Opening of the Fifth Seal.

According to John Richardson, a British art historian, Les Demoiselles d'Avignon "turns out to have a few more answers to give once we realize that the painting owes at least as much to El Greco as Cézanne".

According to Rolf Laesse, this may have been the original inspiration of Picasso who in a preliminary drawing of the Demoiselles depicted a medical student holding a skull or a book and entering a room where there is a sailor among nude women.

[11] Richardson sees the Apocalypse in El Greco's Opening of the Fifth Seal as the catalyst which showed Picasso how to harness the spiritual energy of a great religious artist to his own demonic ends.