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.