According to one Hawaiian legend, Laka, goddess of the hula, gave birth to the dance on the island of Molokai, at a sacred place in Ka'ana. After Laka died, her remains were hidden beneath the hill Pu'u Nana. The annual Molokai Ka Hula Piko festival is still held on the island.

The island developed from two distinct shield volcanoes known as East Molokai and the much smaller West Molokai. The northern half of East Molokai suffered a catastrophic collapse about 1.5 million years ago and now lies as a debris field scattered across the bottom of the Pacific Ocean--but what remains of this volcano includes the tallest sea cliffs in the world.

The kākāwahie or Molokai creeper (Paroreomyza flammea) had the appearance of a ball of flame, especially males, which were scarlet red all around. Native Hawaiians trapped the birds for their red feathers, which were then used in the capes and leis of ali'i (nobles and royalty). It was last sighted in montane wet forest at 'Ōhi'alele Plateau in 1963.

The largest town on the island is Kaunakakai, which is one of two small ports on the island. The town was made famous in the 1930s by the song "The Cockeyed Mayor of Kaunakakai", which was written to celebrate a visit by Academy Award-winning actor Warner Baxter and started an ongoing tradition of designating an honorary mayor for the town.

Although Captain James Cook recorded a sighting of Molokai in 1778, the first European to actually visit the island was Captain George Dixon of the British Royal Navy in 1786. He had previously served under Captain Cook as armourer on the HMS Resolution.

In the late 1800s, Kamehameha V built a vacation home in Kaunakakai and ordered the planting of over 1,000 coconut trees in Kapuaiwa Coconut Grove.

In order to control the spread of leprosy, which had been brought to the islands by Europeans, the Hawaiian government established a leper colony on Molokai that operated from 1866 to 1969. More than 8,500 men, women and children diagnosed with leprosy were exiled to the colony and declared legally dead. Patients weren't allowed to leave the settlement or have visitors and had to live out their days in isolation.

The Phallic Rock (its Hawaiian name is Ka Ule o Nanahoa (meaning "phallus of Nanahoa") has been standing erect for generations at what is now known as the Pala'au State Park. According to legend, this rock is inhabited by the spirit of the fertility god Nanahoa, and women who visit the rock will receive his help in becoming pregnant.

Several other islands are visible from the shores of Molokai, including Oahu from the west shores, Lanai from the south shores, and Maui from the south and east shores.

At 4,961 feet (1,512 m), Kamakou is the highest peak on the island. It is part of the extinct East Molokai shield volcano.