Hetepheres II must have been one of the longest living members of the royal family of the Fourth dynasty of Egypt. She was a daughter of Khufu, probably born during the reign of her grandfather, Sneferu or during the early years of her father's reign. A fragmentary titulary found in the tomb of Meritates , may indicate that Meritates was the mother of Hetepheres II. At the latest during the reign of Khufu, she married her brother Kawab , with whom she had at least one child, a daughter named Meresankh III .

After the death of her first husband, she married another of her brothers, Djedefra. When Djedefra succeeded to the throne, after Khufu' death, Hetepheres II became a queen.

She was widowed again when Djedefre died. She then married Ankhhaf , another member of the 4th Dynasty royal family. The marriage of her daughter, Meresankh III, to her late second husband's successor Khafra made Hetepheres II the mother-in-law of the new king. She also out-lived her third husband and her daughter, Meresankh III. A mark of her affection for Meresankh may perhaps be seen in the fact that Hetepheres II had her own mastaba in the eastern cemetery of Giza converted into a tomb for her daughter.

She finally died early in the reign of Shepseskaf, the son and successor of Menkaura and had thus witnessed the reigns of 5 (perhaps 6, if she was born during the reign of Sneferu) kings of the 4th Dynasty.