Hernando was born in Trujillo, (Extremadura), Spain, son of Captain Gonzalo Pizarro y Rodríguez de Aguilar (senior) (1446-1522) - who as colonel of infantry served in the Italian campaigns under Gonzalo Fernández de Córdoba, and in Navarre, with some distinction - and wife Isabel de Vargas.
As one of the Pizarro brothers, he was related to Francisco, Juan, and Gonzalo Pizarro. He had two full sisters, Inés Pizarro y de Vargas, who married but did not have children with Francisco's only legitimate son, and Isabel Pizarro y de Vargas, married to Gonzalo de Tapia. Through his father, he was second cousins with Hernán Cortés.
Unlike his other brothers, his birth was legitimate, and he was educated and gained influence in the Spanish court. In 1530 Hernando departed for the New World with his half-brother Francisco Pizarro, and accompanied him during his conquests in Peru. In 1533 Hernando was sent back to advance the Pizarro interests against Francisco's uneasy partner Diego de Almagro, as Hernando had the best connections in the Spanish court. When he returned to Peru, he ruled with his other half-brothers (Juan and Gonzalo Pizarro) over the prized Inca capital of Cuzco. Governing with an iron fist, he helped with the eventual suppression of Inca uprisings led by Manco Capac.
After Diego de Almagro returned from Chile on a fruitless gold-seeking expedition, he found that Hernando and his brothers were in control of Cuzco. However, as he had not obtained any credit for having been Francisco Pizarro's main partner in discovering Peru, he decided to claim Cuzco as part of his share. Almagro seized the city in 1537, capturing Hernando and Juan. Hernando was eventually released after negotiations between Almagro and Francisco, and in 1538 he and Gonzalo returned with an army to confront Almagro. In the ensuing Battle of Las Salinas, the Pizarros won a decisive victory, capturing Almagro and the city.
The execution of Almagro later that year and the general disorder caused by the Spanish infighting caused substantial fallout in the Spanish court. Hernando was again called upon to leverage his royal contacts: in 1539 he returned to Spain to lobby in favor of the Pizarros. Their perceived treachery was too great, however, and despite Hernando's bribery, he was imprisoned for the next twenty years. He left prison in 1560 and generally dropped out of sight, reportedly dying at the age of 100 in the year 1608. Other sources suggest he died in 1578, and some that he was 72 at the time of death, which would make the year of his birth 1505 or 1506. If he in fact was 100 years old the year of his birth would be 1478 or 1508.
On October 10, 1537 in Spain, Hernando had married his niece, Francisca Pizarro Yupanqui (she was the daughter of Francisco Pizarro and his Inca mistress Inés Yupanqui; although born illegitimately, she was legitimized by Imperial Decree). With her Hernando had a son: Francisco Pizarro y Pizarro. This son, in turn, married twice and had offspring, the Marqueses de La Conquista; as a result, the Pizarro line survived Hernando's death, though currently extinct in male line.
His father was a son of Fernando Alonso Pizarro and wife Isabel de Vargas Rodríguez de Aguilar, paternal grandson of Fernando or Hernando Alonso de Hinojosa and wife Teresa Martínez Pizarro, and brother of Juan Pizarro, who died without issue in 1521, and Diego Fernández Pizarro, who married Marina López and had a son Fernando Pizarro López, who had a natural son named Diego Pizarro de Vargas, married to Juana Rodríguez de Bobadilla, with female issue in Portugal.