Below Salt Springs it receives the Bear River from the north and then passes through the smaller Tiger Creek Reservoir before joining with the Middle Fork southeast of Pine Grove.

The Mokelumne River watershed drains 2,143 square miles (5,550 km2) in parts of Alpine, Amador, Calaveras, San Joaquin, and Sacramento Counties.

Elevations range from sea level at the confluence with the San Joaquin River to 10,400 feet (3,200 m) at the crest of the Sierra Nevada in the headwaters of the North Fork.

The American, Calaveras and Stanislaus rivers, like the Mokelumne, drain westwards into the Central Valley, while the Carson flows eastwards into the Great Basin.

[9] The Cosumnes River and its own North, Middle and South forks drain about 724 square miles (1,880 km2) in the northern part of the basin, or about 33.8% of the total watershed.

[11] The upper watershed is situated principally in Alpine, Amador and Calaveras Counties and consists mostly of wilderness managed under various federal designations.

There are also significant private holdings in the upper basin including commercial timber land and protected watershed areas administered by the East Bay Municipal Utility District, which diverts urban and industrial water from Pardee Reservoir.

The lower watershed, mainly within San Joaquin and Sacramento Counties, is part of the rich agricultural region of the Central Valley.

In May 2021, it was reported that a trove of 5- to 10-million-year-old fossils was unearthed in June 2020 in the Mokelumne River watershed near Valley Springs, California, including a two-tusked mastodon, a four-tusked gomphothere, rhinoceros, camel, horse, tortoise, tapir, bird, fish, and other specimens.

The lower (western) basin was the most densely populated, with numerous villages between the fringe of the Sierra foothills and the eastern edge of the Sacramento–San Joaquin Delta.

This area is believed to have been predominantly Plains Miwok; various subgroups that lived in the Mokelumne River basin included the Mokellos, Lalas, and Machacos.

[17] The Mokelumne River is home to five notable whitewater kayaking runs: Fantasy Falls, Devil's Nose, Tiger Creek Dam, Ponderosa and Electra-Middle Bar.

Fantasy Falls, a Class V+, 26-mile wilderness reach, runs from below Highway 4 in Alpine County to the backwaters of Salt Springs Reservoir.

The Mokelumne is also a popular site for fishing, camping, water play, birding, picnics, gold panning, spring wildflower watching, and other activities.

The California Office of Environmental Health Hazard Assessment (OEHHA) has developed a safe eating advisory for Lower Mokelumne River based on levels of mercury or PCBs found in fish caught from this water body.

[19] In 1929 the East Bay Municipal Utilities District (EBMUD) built the large Pardee Dam several miles upstream from Lodi and the irrigation diversion points on the Mokelumne River.

Pardee is the primary storage facility and diversion point for the 91-mile (146 km) Mokelumne Aqueduct, which provides water to 35 municipalities in the eastern San Francisco Bay Area in Alameda and Contra Costa Counties.

Through an agreement between EBMUD and local farmers, Pardee also stabilized the dry season water level in the lower Mokelumne, allowing much greater use of the river for agriculture.

Its primary purpose is to provide flood control for downstream communities, which allows more water to be retained in Pardee Reservoir for the Bay Area's use.

The dam regulates releases from Pardee for local uses, primarily irrigation, and provides flood control for the lower Mokelumne River.

[8] In addition to salmon and trout, common native fish include prickly sculpin (Cottus asper), and Sacramento sucker (Catostomus occidentalis).

The non-native western mosquitofish (Gambusia affinis), largemouth bass (Micropterus salmoides) and bluegill (Lepomis macrochirus) are also plentiful.

[25] In its original 2040 long-range water plan, issued in 2009, the East Bay Municipal Utility District approved an optional expansion of Pardee Reservoir [1].

In April 2011, Sacramento Superior Court Judge Timothy M. Frawley ruled in the groups' favor and voided the EBMUD plan.

The East Bay Municipal Utility District initially opposed the bill but supported it with proposed author's amendments late in the legislative process.

The compromise bill was supported by Sierra foothill water agencies, the East Bay Municipal Utility District and river and fish conservation groups.

The final report, issued in April 2018, recommended adding approximately 37 miles of the North Fork and main Mokelumne to the California Wild and Scenic Rivers System.