Juan Rodríguez Cabrillo is believed to be the first European to explore the California coast. He was either of Portuguese or Spanish background, although his origins remain unclear. Cabrillo led an expedition in two ships of his own design and construction from the west coast of what is now Mexico, setting out in late June 1542. He landed on September 28 at San Diego Bay, claiming what he thought was the Island of California for Spain. Cabrillo named each of Californias' channel islands, which lie offshore from Baja California to northern California, as he passed them and claimed them for Spain.

Cabrillo and his crew continued north and came ashore October 8 at San Pedro bay, later to become the Port of Los Angeles, which he originally named the bay of smoke (bahia de los fumos) due to the many cooking fires of the native Chumash Indians along the shore. The expedition then continued north in an attempt to discover a supposed coastal route to the mainland of Asia. They sailed at least as far north as San Miguel Island and Cape Mendocino (north of San Francisco). Cabrillo died as the result of an accident during this voyage; the remainder of the expedition, which may have reached as far north as the Rogue River in today's southern Oregon, was led by Bartolomé Ferrer. Cabrillo and his men found that there was essentially nothing for the Spanish to easily exploit in California, located at the extreme limits of exploration and trade from Spain. The expedition depicted the indigenous populations as living at a subsistence level, typically located in small rancherias of extended family groups of 100 to 150 people.