[11][12] Anthropological evidence suggests Ohlone ethnogenesis occurred around 700 CE following a wave of migration from the Central Valley.

Prior to colonization, the Ohlone did not operate as a single consolidated unit; they identified more with their local tribe and village than with the nation at large.

The several local tribes that lived in the area prior to colonization coalesced into the modern Ramaytush people following the precipitous decline of their population in the 1800s.

In 1595, Philip II of Spain tasked Sebastião Rodrigues Soromenho with mapping the west coast of the Americas.

Soromenho set sail on Manila Galleon San Agustin on July 5, 1595, and in early November they reached land between Point St. George and Trinidad Head.

The expedition followed the coast southward and on November 7 the San Agustin anchored in Drakes Bay, about 40 miles northwest of Millbrae.

On December 8, 80 remaining crew members set sail on the San Buenaventura, a launch which was partially constructed en route from the Philippines.

Seeking the fastest route south, the expedition failed to notice the Golden Gate, arriving at Puerto de Chacala, Mexico on January 17, 1596.

In 1603, this expedition landed in Monterey Bay, about 50 miles southeast of Millbrae, leading to the first documented interaction between the Ohlone people and European explorers.

[18] Little came of this expedition, and for the next 150 years, Alta California remained a distant frontier land, largely outside of the kingdom's control, despite its claims.

José Cabrera Bueno's 1734 Navegación Espéculativa y Práctica describe it with the following:Through the opening in the center enters an estuary of salt water without any breaking of the waves at all, and by going in one will find friendly Indians and can easily take on water and wood.On November 4, 1769, the Portolà expedition climbed Sweeney Ridge and descended southeast parallel to San Andreas Creek before camping overnight near what is today San Andreas Lake and Millbrae's western border.

Over the next few decades, many of the Ohlone people who lived in and around what is today Millbrae relocated to Mission San Francisco de Asís, where they were baptized.

[19] Following this proclamation, the Indigenous people within the military districts of San Diego, Santa Barbara, and Monterey who were found qualified were freed from missionary rule and made eligible to become Mexican citizens.

[20][21] In 1827, Echeandía granted permission for sub-lieutenant José Antonio Sánchez to occupy Mission San Francisco's Rancho Buri Buri—which included parts of present-day Millbrae and Burlingame—for “grazing and agricultural purposes.

"[22] The Mexican Secularization Act of 1833 opened the lands of nearby Mission Dolores to civilian settlement, and the small town of Yerba Buena, which later changed its name to San Francisco, was established that year.

In 1872, members of the Sánchez family built the original Sixteen Mile House, a historical restaurant and rest stop near the Mills estate, and direct link to Millbrae's early days.

The Mills estate was bordered by what is now Skyline Boulevard, U.S. Route 101 (the Bayshore Freeway), Millbrae Avenue and Trousdale Drive.

[27][28][8] Transportation has shaped Millbrae's growth; Legislative Route Number (LRN) 2, which is today known as California State Route 82 or El Camino Real, was established in 1909 largely parallel to the San Francisco and San Jose Railroad,[29] and in 1919, Skyline Boulevard, which runs along Millbrae's western boundary, was established as LRN 55, connecting San Francisco and Santa Cruz via the foothills of the Santa Cruz Mountains.

[30] Construction on the Bayshore Freeway, which runs parallel to El Camino and the SF&SJ railroad tracks, began in 1924 and by 1929, it connected Millbrae with the East Bay via the newly completed San Mateo-Hayward Bridge.

The course provides a green belt in the center of the city that is the home of many animals, such as the red-tail fox, that otherwise would not be able to survive in the urban setting.

In the 1940s, a hilltop was shaved away to produce landfill for the expanding San Francisco Airport, which received an "international" designation in 1954 with the completion of the Central Terminal.

The original Sixteen Mile House was located where Millbrae O'Reilly Auto Parts stands today, at the intersection of El Camino Real and Center Street.

Such challenges, though inevitable, have only strengthened Millbrae's resolve to preserve the city's unique character and rich history.

[40][41] Several chains including Chick-fil-A, Panda Express, Crumbl Cookies, and Starbucks have signed leases to move into the new retail space at the Gateway.

[42][43] Transportation continues to be a large driver of Millbrae's growth; SFO has become one of the busiest airports in the world, Junipero Serra Freeway, El Camino Real, and the Bayshore Freeway remain major thoroughfares between San Francisco and San Jose, and since 2003 Millbrae station has been the only station served by both BART and Caltrain.

[44][45] Millbrae nevertheless largely remains a bedroom community whose residents commute to jobs in various industries throughout the Bay Area.

[46] In addition to the increasing awareness that came with becoming a BART terminus in the early 2000s, the city gained notoriety in the early 2020s following spats with the California High-Speed Rail Authority[47][48] and the San Mateo County government,[49][50] as well as a possible hate crime targeting then councilmember Anders Fung.

[27] According to the National Weather Service, Millbrae enjoys a typical Mediterranean climate featuring cool, wet winters and dry, mild summers.

The nearest National Weather Service station is at the nearby San Francisco International Airport, where records go back to early 1927.

California State Route 82, known more commonly as El Camino Real, runs near the center of the city, including through its downtown.