[4] In 1769, the Spanish exploration party led by Don Gaspar de Portolà camped by the creek for five nights, November 6–11, after their momentous discovery of San Francisco Bay.

The Franciscan missionary Juan Crespí, a member of the expedition, noted in his diary that, "The commander decided that we should stop in this valley while the explorers went out again to acquire certain information...They were given four days to be gone".

Although de Anza discovered Padre Palou's 1774 wooden cross, the creek's summer flow was deemed too low to support a mission.

[16] Its watershed is about 110 square kilometers (42 sq mi) in extent, including areas of San Mateo and Santa Clara counties.

In the late 1920s levees were constructed to re-route the creek through a new engineered channel from its former mouth, to a sharp north turn for about half a mile, then to the northeast, before exiting to the Bay.

[19] The first President of Stanford University, David Starr Jordan, included a rendering of a "sea-run rainbow trout from San Francisquito Creek" in the Pacific Monthly in 1906.

Several lines of evidence support the historical presence of coho salmon (Oncorhynchus kisutch) in San Francisquito Creek.

"[25] Thirdly, Dennis L. Bark, a senior fellow at the Hoover Institution, recalls playing on San Francisquito Creek around 1947: "Salmon swam up it, and in winter it was a dangerous place.

[28] The southern limit of coho salmon in coastal California streams was recently confirmed to extend through Santa Cruz County based on both archaeological evidence and historically collected specimens.

[29] Recent physical evidence utilizing ancient DNA sequencing of salmonid remains proved that the southern limit of coastal Chinook salmon included the southernmost tributaries of South San Francisco Bay.

[31] In 2006, an Aquatic Habitat Assessment and Limiting Factors Analysis commissioned by the Santa Clara Valley Water District concluded that the key factor limiting smolt production within the study area (San Francisquito Creek mainstem and Los Trancos Creek) and potentially throughout the watershed, is a lack of suitable winter refuge in deep pools and large woody debris.

Stanford installed Los Trancos Creek Diversion Dam in 1929, to divert stream flows to its Felt Lake water storage reservoir.

The dam, located just below the intersection of Arastradero and Alpine Roads, blocks access of upmigrating steelhead trout to over 3 miles (4.8 km) of pristine upstream spawning grounds.

[35] Anadromous steelhead trout now access the upper Los Trancos Creek watershed above Rossotti's Alpine Inn Beer Garden.

It was located just north of the east end of Happy Hollow Lane near Alpine Road and near the Stanford Weekend Acres neighborhood in unincorporated Menlo Park.

In 2014 Our Children's Earth Foundation sued Stanford for allegedly violating the Endangered Species Act, saying the dams obstruct steelhead trout from swimming upstream to freshwater habitats necessary in the early stages of their life cycle.

Recently, gray foxes (Urocyon cinereoargenteus) have been documented near the mouth of San Francisquito Creek (see photo) and on the Palo Alto Golf Course.

[42] The flora of the upper watershed consists of scattered oak and madrone woodlands that are intermingled with grassland habitat, in some areas forming a savanna.

A grove of upland coast redwood (Sequoia sempervirens) forest occurs along San Francisquito Creek just below Searsville Lake.

Common native riparian shrubs include coffeeberry (Rhamnus californicus), ocean spray (Holodiscus discolor), and creeping snowberry (Symphoricarpos mollis).