As the Sac and Fox and Iowa reservations were opened to non-Indian settlement in 1891 and the Cherokee Outlet by the 1893 run, Payne County's borders were expanded by adding several townships of the Outlet and several miles of land south of the Cimarron River. These openings also created new counties that now border on Payne-Noble, Lincoln, Creek, and Pawnee. Logan, on the southwest border, was one of the seven original counties. These changes made Payne a part of north-central Oklahoma. The county incorporates 697.13 square miles of land and water area.

Railroads soon crisscrossed the county after the land openings. Two major lines were built by the Eastern Oklahoma Railway between 1900 and1902 and immediately placed under lease to the Atchison, Topeka and Santa Fe Railway. One north-south line connected Pawnee to Stillwater, Ripley, and Cushing Junction and then joined another north-south line that extended from Newkirk through Pawnee County and Payne County to Shawnee. A line from Guthrie to Cushing Junction followed the Cimarron River to Ripley. Thus, as farming developed and rural communities grew up, the railroads provided a means of getting crops to market.

From 1889 to 1902 thirty-three post offices were set up in the county, some of which disappeared within a few weeks. As this occurred, leaders emerged who had great influence on the county's history and its government. These included Robert A. Lowry, a lawyer and newspaper publisher from Angus, Iowa. He was often called the "Father of Stillwater." He donated eighty acres of his claim to secure a townsite, led in forming the first city government, and helped assure Stillwater as the county seat. Frank J. Wikoff, only twenty-two, made the 1889 land run. He wrote the first Stillwater city charter. He was the first city attorney, the first Payne County attorney, and the first county judge, and he later became chair of the Oklahoma A&M College Board of Regents. Capt. William A. Knipe, provided similar leadership in Perkins. For more than forty years he was active in all facets of Perkins's development and led efforts to have the county seat and the land grant college located in Perkins. William R. (Billy Rae) Little planned before the 1891 land run to start a town on the Sac and Fox Reservation. He was among the first to establish a claim after the land run, and he set aside eighty acres of his claim for a townsite that became Cushing. William L. Couch is honored in Stillwater for having established a Boomer colony on the banks of Stillwater Creek in 1884, which he named Stillwater, Oklahoma.

For more than a half century agriculture remained the base of the county's economy. Cotton, corn, and wheat were among the primary crops. Perkins was considered a cotton center.

In 1896 the county's population was 14,192, and by 1910 it had reached 27,735. After that, it increased by several thousand each decade until in 1940 it stood at 36,057. Meantime, Stillwater's population in 1940 had reached 7,000, and the town had found a new economic base as Oklahoma A&M College's enrollment increased to 5,500.

This was to end a half-century era. World War II and its aftermath would drastically change Payne County. The war had been underway only a few months when its threat to Stillwater's economy became apparent. Students by the hundreds left the college to serve in the armed forces. To offset the loss, a delegation of city and college leaders went to Washington, D.C., and, after visits with military leaders and U.S. Sen. Almer Stillwell "Mike" Monroney, were able to have the college designated a war training center. Their efforts were successful, and twelve training programs involving nearly forty thousand naval personnel were approved for the college. While this guaranteed the survival of both the city's and college's economies through the war era, it caused its leaders to realize that a diversified economic base was essential for the future.

In 1951 they established an Industrial Foundation whose function was to bring manufacturing plants and industrial jobs to Stillwater. The foundation's success was phenomenal. From 1966 to the turn of the twenty-first century thirteen major manufacturers and other smaller ones established plants in Stillwater, creating more than five thousand jobs. Meanwhile, the college, now known as Oklahoma State University, had also grown and its personnel exceeded seven thousand by 2000. 

The county is especially known historically for several events. Area historians have found artifacts they believe prove that the first battle of the Civil War in Oklahoma, Round Mountain, was fought near the Twin Mounds area west of Yale. In 1893 a battle between outlaw Bill Doolin's gang and lawmen was fought at Ingalls. Three marshals were killed. In the early 1920s Cushing, Yale, and Ripley were hotbeds of Ku Klux Klan activities. As many as three thousand members attended some rallies. Incorporated towns included Cushing, Glencoe, Pershing, Ripley, Stillwater, and Yale. Residents found recreational activities offered at Lake McMurtry and Lake Carl Blackwell. Among the numerous Payne County properties listed in the National Register of Historic Places are the Payne County Courthouse (NR 84003410), the Hopkins Sandstone House and Farmstead near Ripley (NR 79002017), Irving's Castle near Ingalls (NR 78002257) and Cottonwood Community Center near Stillwater (NR 80004291).