The first and most prominent Protogeneia was a Phthian princess, the daughter of King Deucalion of Thessaly and Pyrrha, the mythological progenitors of the Hellenes. As a child of the flood survivors, she belongs to the first generation of the renewed human race.

Her siblings included Hellen and Amphictyon, as well as Pandora the Younger, and possibly Thyia, Melantho (also called Melanthea), and Candybus. The genealogy of Deucalion's children varies among the ancient authors, and Protogeneia's place within it is recorded chiefly by Apollodorus (Bibliotheca 1.7.2).

By Zeus, Protogeneia became the mother of Opus, Aethlius, Aetolus, and possibly Dorus. Different sources assign her different children: Hyginus (Fabulae 155) names Aethlius and Aetolus among Zeus's offspring, a scholion on Pindar's Olympian Odes (9.85) makes Opus her son, and the pseudo-Clementine Recognitions list her as the mother of Opus, Aethlius, and Aetolus.

A second Protogeneia, also called Cambyse, was the daughter of the Opus mentioned above. Zeus carried her away from the lands of the Epeans and fathered a son, Opus II, with her on Mount Maenalus in Arcadia.

She was afterward married to Locrus, who adopted her son Opus as his own.

A third Protogeneia was a Calydonian princess, the daughter of King Calydon and Aeolia, who was herself a daughter of Amythaon. This made her the sister of Epicaste.

By the god Ares she became the mother of Oxylus of Aetolia.

A fourth Protogeneia was the eldest of the daughters of King Erechtheus of Athens. She and her sister Pandora were sacrificed on a hill called Hyacinthus, and the two came to be known as the Hyacinthids.