He held a command in the Juan de Grijalva expedition sent from Cuba against Yucatán in the spring of 1518, and returned in a few months, bearing reports of the wealth and splendour of Montezuma's empire.
In February 1519 he accompanied Hernando Cortés in the expedition for the conquest of Mexico, being appointed to the command of one of the eleven vessels of the fleet. He acted as Cortés's principal officer, and on the first occupation of the Aztec capital city of Tenochtitlan was left there in charge. When the Spaniards had temporarily to retire before the Mexican uprising, Alvarado led the rear-guard (July 1, 1520), and the Salto de Alvarado--a long leap with the use of his spear, by which he saved his life--became famous.
He was engaged in the conquest of the highlands of Guatemala from 1523 to 1527. At first Alvarado allied himself with the Cakchiquiel nation in his conquest of their traditional rivals the Quiché nation, but his cruelties alienated the Cakchiquiel, and he needed several years to stamp out resistance in the region. He was subsequently appointed governor of Guatemala by Charles V.
In 1534 Alvarado heard tales of the riches of Peru, headed south to the Andes and attempted to bring the province of Quito under his rule. When he arrived he found the land already held by Pizarro's lieutenant Belalcazar. The two forces of Conquistadors almost came to blows, but then Pizarro paid off Alvarado to leave.
During a visit to Spain, three years later, Alvarado had the governorship of Honduras conferred upon him in addition to that of Guatemala.
Alvarado fought to suppress a major revolt by the Mixtón natives of the Nueva Galicia region of Mexico, where he was badly wounded in battle on June 24, 1541. Accounts differ as to whether he was still alive or already dead when he was carried back to Guatemala, but at any rate he was buried in Antigua Guatemala in 1541.