The road to the La Jolla campus was not smooth. When UC Regents first authorized a San Diego campus in 1956, the plan called for a graduate institution focused on science and engineering. Roger Revelle, then director of Scripps Institution and the primary advocate for the new campus, nearly derailed the site selection by publicly exposing La Jolla's discriminatory real estate practices — the community had been actively excluding minority racial and religious groups from buying homes. This outraged local conservatives, including powerful Regent Edwin Pauley. The conflict over whether the university should be purely technical or broadly educational was settled by compromise: General Dynamics pledged a million dollars for a technical school, and the city offered free land for a more traditional university. The compromise language — a graduate program in science and technology that also included undergraduates — satisfied both sides. Classes began in 1964.

The iconic building at the center of campus is Geisel Library, an inverted pyramid of reinforced concrete hovering above a glass base — a 1970 design by William Pereira that looks, from certain angles, like a space station or a modernist chess piece. It was renamed for Theodor Geisel, better known as Dr. Seuss, following a $20 million donation from his widow Audrey Geisel in 1995. Dr. Seuss himself lived and worked in La Jolla, and his presence is woven into campus culture in ways beyond the building's name. The eight undergraduate residential colleges surrounding the library each have distinct architectural characters — a deliberate policy that, as the campus grew through the decades, produced an ensemble of styles so varied that Travel + Leisure magazine named UCSD one of the ugliest campuses in America in 2013, likening it to "a cupboard full of kitchen appliances whose function you can't quite fathom." The university took it in stride.

UC San Diego's research output is disproportionate to its age. The university helped develop UCSD Pascal, an early programming language that directly influenced Java. Its researchers worked on the National Science Foundation Network, an important precursor to the Internet. The San Diego Supercomputer Center, founded in 1985, was one of the first national facilities for high-performance computing in scientific research. Scripps Institution of Oceanography — one of the world's largest and most respected earth science research centers — predates the university itself, having been founded in 1903, and was absorbed into the UC system as UCSD's anchor. The National Science Foundation ranked UCSD seventh among American universities for research expenditures in 2021, with $1.42 billion. For a campus that did not exist until 1960, that rank places it ahead of institutions founded in the eighteenth and nineteenth centuries.

Under Chancellor Richard Atkinson's leadership from 1980 to 1995, UCSD transformed its relationship with San Diego itself. Technology transfer agreements with developing companies helped turn San Diego into a world leader in biotechnology and telecommunications — Qualcomm, whose founder Irwin Jacobs gave his name to the engineering school, was among the companies that grew in the shadow of the university's research programs. The Sycuan Band of the Kumeyaay Nation later co-owned San Diego FC, an MLS expansion team, alongside major investors including baseball star Manny Machado. That kind of regional institutional density — university, tribal enterprise, professional sports — reflects how thoroughly UCSD has become embedded in the economic and cultural life of the city it was once separate from.