Mendoza had commissioned Ruy López de Villalobos in 1541 to lead an expedition to the "Islas del Poniente" (present-day Philippines).

The Spanish navigator departs on October 25, 1542 from Barra de Navidad, New Spain, with his fleet of six ships—the Santiago (the flagship), Jorge, San Antonio, San Cristobal, San Martin and San Juan de Letra—and three hundred and seventy to four hundred men.

López de Villalobos’ fleet heads towards Revillagigedo Islands off the west coast of Mexico and on December 25, sights low islands thought to be Saavedra's “Los Reyes.” The following day, they see a group of islands at 9° or 10°N which they name "Corrales,” anchoring at one of these.

López de Villalobos sights ten islets on the same latitude, appearing so beautiful that they name them "Los Jardines" (The Gardens), on January 6, 1543. (This was probably Eniwetok, according to historian Martin J. Noone.)

Between Eniwetok and ...

...Ulithi, during the period between January 6 and 23, the galleon San Cristobal piloted by Gines de Mafra (who had been a member of the crew of the Magellan expedition in 1519-1522) is separated from the fleet during a severe storm.

This ship ultimately reaches the island of Mazaua, the anchorage of the Magellan expedition in March-April 1521, where Magellan and his crew had been received with great "urbanity," as chronicled by Antonio Pigafetta, the Vicentine diarist who wrote the most comprehensive eyewitness account of Magellan's voyage.

This is the second visit of de Mafra to this island, which is sometimes mistakenly identified today as Limasawa in southern Leyte; the location and identity of Mazaua remains a mystery.

The men spend the next four to six months at the hospitable little isle.

De Mafra, in his account, relates he again met the "king" of Mazaua, named "Siaiu" by Pigafetta, who showed to de Mafra the items Magellan had given him as gifts, namely a "robe of red and yellow cloth, made in the Turkish fashion, and a very fine red cap," as enumerated by Pigafetta.

The Spanish fleet enters Baganga Bay (which they name Malaga) on east Mindanao on February 29.

López de Villalobos names Mindanao Caesaria Karoli after the Holy Roman Emperor, Charles V of Spain, because it looks so majestic.

The fleet stays here  thirty-two days, the entire crew suffering extreme hunger.

The fleet leaves on March 31 in search of Mazaua, which had become famous for its friendly and generous reception to the Magellan fleet, but northerlies prevent them from making any headway.

After a ten-day struggle, ...

...they drop down and reach Saranggani.

The San Cristobal, to the delight and relief of everyone, appears out of nowhere around the first week of July, bringing food from Mazaua.

The San Juan and San Cristobal leave for Leyte on August 4.

A Portuguese contingent arrives on August 7, and delivers a letter from Jorge de Castro, governor of the Moluccas, demanding an explanation for the presence of the fleet in Portuguese territory.

López de Villalobos responds, in a letter dated August 9, that they are not trespassing and are perfectly within the Demarcation Line of the crown of Castile.

The San Juan leaves for Mexico on August 27, with Bernardo de la Torre as captain.

Another letter from Castro arrives in the first week of September with the same protest, and López de Villalobos writes a reply dated September 12 with the same message as his first.

He quits Sarranggani to go to Abuyog, Leyte with his remaining ships, the San Juan and the San Cristobal but again, the fleet cannot make headway because of unfavorable winds.

Spanish navigator Ruy López de Villalobos meanwhile discovers the thirty-odd Bonin, or Ogasawara, Islands, a volcanic, mountainous archipelago located about five hundred miles (eight hundred kilometers) south of Tokyo.

There are two other visits by members of the Villalobos expedition to Mazaua.

The galleon San Juan, under Bernardo de la Torre, pays a brief visit some time in April 1544 in search of the main contingent of the expedition.

Another visit is by the brigantine under Captain Garcia Escalante de Alvarado around September–October 1544 in search also of the some members of the expedition who had been left in Sarangani.

López de Villalobos leaves in April 1544 for the island of Amboyna in the Moluccas.

He and his crewmembers make their way to ...

...the islands of Samar and ...