It goes through Rumsey, Guinda, Brooks, Cache Creek Casino Resort, Capay, Esparto (intersecting with County Route E4 to Dunnigan), and Madison.

At the junction with US 50 in the southeastern part of Downtown Sacramento, SR 16 turns eastward on an unsigned concurrency with US 50.

After it passes near Sloughhouse and Rancho Murieta, where it crosses the Cosumnes River, SR 16 enters Amador County.

[9] The two ends of SR 16 were added to the state highway system by the third bond issue, passed by the state's voters in 1919: Route 50 from Lower Lake east to Rumsey and Route 54 from the Sacramento-Amador County line east to Drytown.

[11] Although the exact alignment of Route 50 was not specified, the state Department of Engineering had already surveyed a 35-mile (56 km) route through Cache Creek Canyon pursuant to a 1915 law, which defined the Yolo and Lake Highway "following generally, the meanderings of Cache creek" but did not make it a state highway.

[23] After this, SR 16 was rerouted from the intersection with County Route E7 to continue north on a bypass of Woodland instead of east to Interstate 5.

[24] Except where prefixed with a letter, postmiles were measured on the road as it was in 1964, based on the alignment that existed at the time, and do not necessarily reflect current mileage.