Its earliest known inhabitants were the Patwin Native American tribe, of a population believed to have never exceeded 5000.

The Napa Valley was to later be explored by the first Europeans, Francis Castro and Father Jose Altimura in 1823. When settlers later arrived in the 1830s, there were 6 warring tribes, followed by a smallpox epidemic in 1838, and clashes with the settlers would greatly reduce this local population. By 1847, the town was founded on the Rancho Entre Napa land grant from Mexico.

The first commercial winery in the Napa Valley was opened by John Patchett in 1859. One of his winemakers, Charles Krug, would also found his own winery in St. Helena two years later, which later became the winery where Robert and Peter Mondavi's got their start. Robert eventually moved on to his own 'Robert Mondavi WInery', while Peter kept Charles Krug, and to this day can be seen meandering the property.

The population was to grow in the mid-century years as pioneers, prospectors, and entrepreneurs moved in and set up residence. As much as raising cattle and farming grain and fruit crops were the major economic activities of the settlers, silver mining also brought in substantial income to the new residents with large-scale mines running through the 1860s. Agriculture was diverse in nature in the county ranging from plumbs grown for Sunsweet prunes, to Walnuts and grapes. The current wine fame Napa Valley holds, started with the famous "French Competition" in the late 1970's, growing in popularity late in the 1990s when wine grapes became the primary focus. Over 90% of the agricultural land was vineyards but at the end of the 20th century, with modern-day farmers explored the raising of other food crops such as olives.

With film festivals, food festivals, music festivals, art festivals, and the inevitable wine festivals, the place is a befitting place to set up residence for wine, food and the epicurian-lifestyle individuals.