[2][3] He pioneered amphibious warfare and strategic usage of several kinds of ships, refining the design of existent vessels and popularizing galleons as warships, ultimately making possible many of the successes of the Spanish Empire since the 16th and 17th centuries.

[3] He built the Palace of the Marquis of Santa Cruz in Viso, Spain, which currently houses the General Archive of the Spanish Navy.

Bazán's father took part together with Giovanni Andrea Doria and others marines in the recapture of Tunis in 1535, and was distinguished in the service of Charles V, by whom he was made general of the galleys, or commander-in-chief of the Spanish naval forces in the Mediterranean.

Bazán the Elder suggested to no effect that Gibraltar's Line Wall Curtain be extended to the southern tip of the rock.

When Philip II enforced his claim as heir to the crown of Portugal in 1580–1581, Santa Cruz held a naval command but António, Prior of Crato, an illegitimate representative of the former Portuguese royal family, who conducted some popular resistance to the crowning of what was seen as a foreign king, continued to hold the islands of the Azores.

[7] Badly outnumbered, he won the Battle of Ponta Delgada off Terceira Island against a loose confederation of Portuguese, French, English and Dutch adventurers and privateers, which decided the struggle for the Azores in favor of the Spanish Habsburgs.

Santa Cruz, who recognized that England presented a grave threat to Spain's empire, became a zealous advocate of war.

A letter written by him to King Philip from Angra do Heroísmo in Terceira, on 9 August 1583, contains the first definite suggestion of the Spanish Armada.

The hesitant character of the king, and his many embarrassments, political and financial, caused many delays and left Santa Cruz unable to take action.

The king was offended by Santa Cruz's independence of judgment, and he held the admiral responsible for the failures and delays, although these are better attributed to the Crown.

In the episode "The Enterprise of England" in the 1971 BBC series Elizabeth R, he is portrayed by Geoffrey Wincott in a historically accurate script, in which King Philip's meddling clearly dooms his plans and exacerbates his declining health.