The Spanish explorer Alvaro-de-Mendana sighted Santa Isabel in February 1568 and after anchoring in a harbour the following day, called it Estrella Bay, and Santa Isabel after the patron saint of his voyage.

Relationships between the Spaniards and the islanders were initially friendly and the visitors were impressed by the local chief who wanted to learn Spanish and promised to supply food in return.  However when insufficient supplies came, the Spaniards seized hostages to trade for extra food.  When violence ensured, together with the Spaniards disgust at the islanders' cannibalism and worship of lizards, snakes and crocodiles, this prompted them to depart after only two months.

During their stay, the Spaniards penetrated deep inland in search of gold, reaching Santa Isabel's central ridges with claims of some fraternization resulting in a smattering of Spanish blood in today's population which is more likely associated to past contacts with Polynesians.

The friendly "Thinking Rat" which lives at the top of tall trees, and eats nuts and fruits, is endemic to Isabel Province, although there is a related species in Guadalcanal.

The people of Isabel Province are Melanesians with 75% living in Santa Isabel's south eastern corner.  Tapa cloth is made locally from the bark of the paper-mulberry trees and tinted a light blue using a dye made from crushed orchid leaves.  Inheritance is matrilineal in Isabel Province, with ownership of land passed on through the mother. This system developed during headhunting days when women's lives were usually spared during raids.