Despite its relative isolation, the island has been witness to many important historical events from the colonial period through to the modern age.

Santa María Island was called Tralca or Penequen by the indigenous Mapuche inhabitants, who were most likely the Nagche, also known as Araucanian, people.

[2] In 1599, Dutch explorer and merchant Simon de Cordes ordered his fleet to stop at the island for supplies and to make repairs during their disastrous circumnavigation attempt.

After landing on Chiloe Island, Brouwer made a pact with the Mapuche, who were then fighting in the War of Arauco against Spain, to aid in establishing a resettlement at Valdivia.

[4][5] On 26 October 1818 First Chilean Navy Squadron under the command of Manuel Blanco Encalada and captured several ships of a Spanish convoy carrying men and weapons for El Callao off the coast of the island.

The Battle of Coronel was fought to the northwest of the island on November 1, 1914, in which the East Asia Squadron (Ostasiengeschwader or Kreuzergeschwader) of the Imperial German Navy (Kaiserliche Marine) commanded by Vice-Admiral Graf Maximilian von Spee met and overpowered a British squadron commanded by Rear-Admiral Sir Christopher Cradock.

Measurements taken after the quake indicated coastal uplifts of between ~0.2 to 3.1 m. A similar phenomenon was documented in 1839 after the 1835 earthquake in the region by Charles Darwin.