Clemson's plan for the school very nearly did not pass. The South Carolina General Assembly was deeply split on the idea of redirecting federal Morrill Act funds from South Carolina College, now the University of South Carolina, to a new agricultural college in the upstate. Benjamin Tillman lobbied hard for the bill. Tillman was a populist agrarian, a future governor, and a key architect of post-Reconstruction white supremacy in the state; his presence at the founding of Clemson is part of the institution's complicated origin story. The bill passed by one vote. Henry Aubrey Strode became the first president in 1890. The school he opened in 1893 was all-white, all-male, and a military institution. It would stay that way for sixty years.

Clemson's first half-century carried the marks of its military structure. Reserve Officers' Training Corps arrived in 1917; thousands of Clemson students would serve in both world wars, with 376 killed in World War II alone. The campus saw two major student walkouts. In March 1920, students walked out to protest what they called prison-camp-style military discipline, which produced a new Department of Student Affairs. In October 1924, around 500 students walked out demanding better food, the dismissal of the mess officer, and the reinstatement of their senior class president; the result was 23 expulsions and 112 suspensions. Two major fires destroyed academic buildings in the mid-1920s. The agricultural building burned in 1925, taking research projects and an agricultural museum with it. Mechanical Hall burned in 1926. The reconstruction produced Sikes Hall and Freeman Hall, which still anchor the historic campus core.

Black applicants had been trying to enroll at Clemson since at least 1947, when one student briefly slipped through what the registrar later called a clerical error and then was never allowed to actually attend. The 1948 admissions debate inside Clemson's board landed where southern boards usually landed: maintain segregation, redirect Black applicants to South Carolina A&M. Through the 1950s, the rejections of applicants like Spencer Bracy, Edward Bracy, and John L. Gainey became newsworthy items in a slowly changing region. Then came Harvey Gantt. Gantt and Cornelius Fludd applied to transfer to Clemson in 1961 and were rejected. They worked with the NAACP. The 1962 lawsuit reached the Fourth Circuit, which in January 1963 ordered Clemson to admit Gantt. The university's administration, having watched the Ole Miss riot of 1962, urged students to remain nonviolent. The desegregation went, by southern university standards, smoothly. Lucinda Brawley became the first Black woman admitted later that same year. Gantt would later become the first Black mayor of Charlotte and a longtime architect.

Memorial Stadium opened in 1942 with 20,500 seats, expanded over decades into the largest stadium in the Atlantic Coast Conference. The nickname Death Valley comes from a combination of the location, a valley in the western part of campus, and the original presence of the Clemson University cemetery on the hill that once overlooked the field. Howard's Rock sits at the top of The Hill at the east end of the stadium. Frank Howard, the head coach who gave the stadium and the team much of its identity, was given the rock in the early 1960s by a friend as a sample from Death Valley, California. He used it as a doorstop for several years until 1966, when he was cleaning his office and told IPTAY executive director Gene Willimon to throw it out. Willimon placed it at the top of the hill instead. Players rub it before games and run down the hill to the field, a tradition Brent Musburger once called the most exciting 25 seconds in college football. The Tiger Paw logo dates from 1970.

Clemson is classified R1 for very high research activity, the highest tier in the Carnegie classification. The nine colleges include Engineering, Computing and Applied Sciences; Agriculture, Forestry and Life Sciences; the Wilbur O. and Ann Powers College of Business, renamed in 2020 after a 60-million-dollar gift; and the new Harvey S. Peeler Jr. College of Veterinary Medicine. The Clemson University International Center for Automotive Research, on a 250-acre campus in Greenville, conducts automotive engineering research with BMW, Michelin, IBM, Bosch, and other corporate partners. The main campus covers 1,400 acres in the foothills of the Blue Ridge, bordered on the west by Lake Hartwell, which appeared in 1962 when the Army Corps of Engineers dammed the Savannah River. The Calhoun Honors College, founded in 1962, was originally named for John C. Calhoun. The university renamed several Calhoun-associated facilities in 2020. Fort Hill itself remains on the National Register, in the middle of campus, the house at the center of every conversation about who the university was and what it is becoming.