In July 1775, Virginia formed the District of West Augusta on the western frontier. In October 1776, West Augusta was subdivided into three large counties, Monongalia, Yohogania, and Ohio. Since that time many counties in Pennsylvania and present West Virginia have been formed from the original Monongalia County. The county's present size is 365.8 square miles.

The first European-American settlement in what is now Monongalia County was made in April 1758 by Tobias Decker with a party of 50 people. They built cabins where Deckers Creek enters the Monongahela River, the present site of Morgantown. Delaware Indians raided this settlement in October 1759, and the survivors scattered, finding safety in other settlements nearby. During the 1760s, several permanent settlers established homesteads. In 1766, Zackquill Morgan registered a land claim. In 1783-84, he had surveyor Maj. William Haymond divide this land into building lots and streets, and in 1785 legislation establishing Morgan's Town was enacted. Indian raids continued until 1791, and at an early date Kerns Fort was constructed on the east side of Deckers Creek.

In November 1814, Monongalia Academy was established, and in 1831 the trustees also formed Morgantown Female Collegiate Institute. Both schools flourished, and Morgantown became known as an educational center. In 1858, Presbyterians established a second school for females, Woodburn Female Seminary. When West Virginia was formed, June 20, 1863, the legislature made plans to establish a federal land grant college under the terms of the Morrill Act. Several towns expressed interest in having the college, but Morgantown officials backed up their request by pledging the buildings and resources of Monongalia Academy and Woodburn Female Seminary to the new college. Thus on February 7, 1867, West Virginia Agricultural College was established. In 1868, the name was changed to West Virginia University.

In the 1790s, iron ore was discovered on Chestnut Ridge, and by 1798 the Davis furnace was in operation, producing a ton of iron daily. An iron community sprang up on the Cheat River at Ices Ferry, which at its peak in the 1840s had a population of 2,500. There were three other furnaces, the Woodgrove, Henry Clay, and Anna. Ices Ferry had a foundry, rolling mill, and nail factory. This industry prospered until 1848 and then operated intermittently until 1868.

During the Civil War, Monongalia County staunchly supported the Union, supplying many more men for the northern armies than for the Confederacy. On April 28, 1863, several hundred Confederate soldiers under the command of Gen. William "Grumble" Jones raided Morgantown to steal horses, cattle, and supplies, and to try to capture Waitman T. Willey, U.S. senator for the Reorganized Government of Virginia. Fortunately, Willey had left for Washington earlier that morning. Troops remained in the Morgantown area for two days, looting stores and rounding up horses, and then left in the direction of Fairmont.

The first railroad reached Morgantown in 1886. This was a branch of the Baltimore & Ohio, which had extended north along the east side of the Monongahela River from Fairmont. This line was completed to Connellsville, Pennsylvania, by 1894, providing through service to Pittsburgh. By 1906, the Morgantown & Kingwood Railroad was running regular trains to Kingwood, continuing on to the main line of the B&O at Rowlesburg. By 1912, the Monongahela Railroad had been completed to Pittsburgh, opening up the rich coal reserves on the western side of the river.

In 1889, the first oil was discovered in Monongalia County. Under the advice of I. C. White, professor and state geologist, an oil well was drilled on Doll's Run near Core. This well was so productive that within three months there were 20 other wells nearby, and natural gas found with the oil was being diverted for commercial use. The oil and gas industry expanded farther and farther into western Monongalia County, and many boom towns sprang up and flourished until their wells gave out. By 1890, the rapid expansion of the oil and gas industry resulted in establishing a vast tank field southeast of Morgantown that at its peak could store more than a million barrels of oil.

The excellent transportation, large supply of cheap natural gas, and deposits of glass sand found along Deckers Creek persuaded the Seneca Glass Company to move from Ohio to Morgantown in 1896. Other glassmakers soon followed, some making fine lead glass, known for its sparkle, brilliance, and good etching character. Others produced soda-lime glass for tumblers, tableware, windshields, canning jars, glass stoppers, and other utilitarian products. The industry thrived for nearly a century, until foreign imports reduced demand. Morgantown glass was known worldwide for its beauty and workmanship.

Efforts to build navigation locks on the Monongahela started in the 1840s near Pittsburgh, and continued slowly toward the headwaters. By 1889, navigable slack water had been extended to the Morgantown area, and regular riverboat service to Pittsburgh was established. Passenger service continued for many years, but competition from railroads made river travel less attractive. Today only freight moves on the Monongahela, including coal and limestone.

By 1890, a coal mine had opened at Beechwood, along the B&O Railroad near the Marion County line, and extensive coal mining was later stimulated by the demands of World War I. Completion of the Monongahela Railroad and discovery of the thick, accessible Pittsburgh coal seam on Scotts Run attracted many large mines and thousands of workers. Monongalia was a leading coal producer for half a century, adding greatly to the economic development of the area, and some production continues today in the western part of the county. In 2021, Monongalia produced 3.8 million tons of coal, ranking it eighth among West Virginia counties.

From the first, the university expanded, but the most spectacular development occurred after World War II, when enrollment doubled and large-scale expansion programs became a reality. The purchase of land for the Evansdale and Medical campuses in the late 1940s and the continuous stream of new buildings have made Morgantown a leader in many fields of higher education. A unique feature of the university is the PRT, or Personal Rapid Transit System, which connects the three campuses. Running on elevated tracks, these modern, rubber-tired cars operate on their own to help meet university transportation needs.

Although much significant research is carried on throughout the university, the medical center, with its teaching and research facilities and hospitals, has gained particular fame. Among their facilities are the Mary Babb Randolph Cancer Center and the John Michael Moore Trauma Center, which are known for their facilities and significant contributions to state-of-the-art medical techniques and knowledge. For 55 years, Mylan Pharmaceuticals, one of the country's major drug makers, operated facilities near the university campus. In 2019, Mylan merged with Pfizer's Upjohn division, creating a new company, Viatris Inc., which became the owner of Mylan. In 2021, Viatris shut down Mylan’s Morgantown facilities, eliminating nearly 1,500 jobs.

Monongalia County's largest employers were WVU Medicine, West Virginia University, Joshua White Enterprises, the county school system, and Mon Health (Vandalia Health).

Interstates 79 and 68 converge at Morgantown, providing high-speed highway travel to the north, south, and east. In 2020, Monongalia County’s population was 105,822, a 29.2 percent increase since the beginning of the 21st century. It is the third largest and one of the fastest-growing counties in West Virginia.