Luis de Moscoso Alvarado, who assumed command of Hernando De Soto's expedition upon the latter's death, was born in Badajoz, Spain, in 1505, the son of Alonso Hernández Diosdado Mosquera de Moscoso and Isabel de Alvarado (otherwise given as Isabel de Figueroa), natives of Zafra. A nephew of the noted conquistador Pedro de Alvarado, Moscoso married his first cousin, Leonor de Alvarado, the daughter of Pedro de Alvarado's brother Juan and the widow of Gil González de Ávila. He had two brothers in the Soto expedition, another Juan de Alvarado and Cristóbal de Mosquera. Little is known of Moscoso's early career. After joining his famous uncle in New Spain, he followed him into Peru and there became associated with Soto. When discord between the Almagros and the Pizarros caused Soto to return to Spain in 1536, Moscoso followed. In Spain he squandered in riotous living the riches he had obtained in Peru and was afterward ready to undertake a new conquest with the prospect of restoring his wealth. He commanded one of the seven ships in Soto's fleet, which sailed from the Spanish port of Sanlúcar de Barrameda on April 7, 1538, bound for Florida via Cuba. In the inland march, he held the position of maestro de campo (field commander) until the disaster among the Chickasaws of northern Mississippi in March 1541. This affair, in which much of the horse herd and twelve Spanish lives were lost, was blamed largely on his negligence. The dying Soto nevertheless chose Moscoso to succeed him as commander of the army. As such, Moscoso acceded readily to the desires of his men to withdraw.
On June 5, 1542, they left Soto's burial place on the Mississippi and marched westward, hoping to reach New Spain. The course took them over "150 leagues," through country determined by the Indian names to have belonged to Caddoan peoples. From "Naguatex," probably in northwestern Louisiana, the route turned south to the country of the Ais (Eyeish) Indians and the Hasinai Confederacy, the focus a century and a half later of the Franciscan missions in eastern Texas. The expedition traveled thence southwest until October, penetrating Texas perhaps as far as the Brazos River, before turning back. The lack of an interpreter and poor prospects for provisions in the country ahead caused them to retreat again to the part of the Mississippi where Soto had died and there to build seven bergantines, or pinnaces, with which to seek a water route to Mexico. On July 2, 1543, 322 survivors of some 600 soldiers and servants who had landed in Florida four years previously boarded the boats and began the descent of the Mississippi. Fifty-three days later, on September 10, the small fleet reached the Pánuco River. They had followed the coasts of Louisiana and Texas and probably entered Matagorda and Aransas or Corpus Christi bays. On reaching Mexico, Moscoso wrote two brief letters to the king, but they shed little light on the expedition. Moscoso's marriage to his cousin, by all accounts a woman of substantial means, occurred sometime later in Mexico. He entered the service of Viceroy Antonio de Mendoza and accompanied him in 1550 to Peru, where he died the following year.