Keahikuni Kekauʻōnohi was born circa 1805 as the daughter of Kahōʻanokū Kīnaʻu and Kahakuhaʻakoi Wahinepio. Her father was a son of a King Kamehameha I, the founder and first ruler of the Kingdom of Hawaii. Her Christian name was either Mikahela or Miriam.
She married her uncle, King Kamehameha II, becoming one of his five wives. King Kamehameha was also married to Kamāmalu (his half-sister), Kīnaʻu (his half-sister), Kekāuluohi (his cousin) and Kalanipauahi (his niece). He was the last Hawaiian King to practise polygamy, and he would never convert to Christianity. His favourite wife was reportedly his half-sister Kamāmalu. King Kamehameha II died in 1824, leaving behind no issue and five young widows. Kekauʻōnohi was still only around 19 years old.
Kekauʻōnohi went to the island of Kaua’i to live with her half-brother Kahalaiʻa Luanuʻu who was serving as governor of the island. She was probably married to him around this time but was widowed for a second time when he died in 1826. In 1832, she married for a third time to Kealiʻiahonui, a member of the nobility of the Kingdom of Kauaʻi and the Kingdom of Hawaii, and the widower of Queen Kaʻahumanu. After his death in 1849, she remarried to Levi Haʻalelea, another member of the Hawaiian nobility. He had served as private secretary and land agent to her third husband. She had one short-lived son, William Pitt Kīnaʻu II, though it seems unlikely that he was the son of her fourth husband, considering she was in her 40s when they married.
Kekauʻōnohi also followed the tradition of hānai adoptions and had three adopted daughters. They were her nieces, Abigail Maheha, Mary Ann Kiliwehi and Anna Kaiʻulani. Between 1842 and 1845, Kekauʻōnohi served as Royal Governor of Kauaʻi. After a significant reshuffle of land in 1848, Kekauʻōnohi was given the second-largest land allotment, making her the greatest landholder after the King and subsequently also inherited property from relatives. She was by then one of the most powerful women in Hawaii and was known to be benevolent, liberal and generous.
She died of unknown causes on 2 June 1851 in Honolulu at the age of 46. She was buried on 30 June 1851, first on the tiny island of Mokuʻula before being moved to Waineʻe Cemetery. She was survived by her fourth husband, who remarried in 1858 to Anaderia Amoe Ululani Kapukalakala Ena.