Dennis's mentor, Owen Wangensteen, was renowned not only for his own contributions to surgical science, but for training imaginative, innovative surgeons, who would in turn become leaders in surgical education. Thus, in 1950, when the dean of the newly established State University of New York (SUNY) medical center in Brooklyn needed a new chairman for the department of surgery, he recruited one of Wangensteen's most talented trainees: Clarence Dennis. Dennis arranged to start at SUNY in August 1951, after his first clinical trials with the heart-lung machine.

The SUNY Downstate Medical Center was developed from the Long Island College of Medicine, a small school founded in 1860 as part of the Long Island College Hospital. The older institution had been one of the first to make clinical training a standard part of medical education, and by 1915 it had admitted women students, and added some post-graduate programs. The new SUNY incarnation, however, was to be a major modern medical research institution with a large basic sciences building and other facilities, as well as competitive residency programs. Dennis would be able to carry on his research, but would also be responsible for upgrading the surgical faculty and the residency program, and designing the new laboratory spaces.

The first few years at SUNY were difficult for Dennis. Although the dean provided ample lab space for his research (in a former mortuary building, as the new science building construction hadn't yet begun), the referrals of cases promised by two local cardiologists did not materialize (both had second thoughts when Dennis's earlier trials with the heart-lung machine failed.) There were political struggles between the old and new medical school faculty members, and with staff at the affiliated hospitals. For example, the medical staff at Kings County Hospital, Downstate's main teaching facility, had two divisions: University and Open, representing academic and non-academic practitioners respectively. The latter felt threatened by the former, and the hospital director was reluctant to favor one over the other. Dennis thus found that some of his equipment, such as a rapid film changer for radiographic studies, had to be made available to the non-academic staff, and that his pump-oxygenator would have to be reconstructed of stainless steel because the director thought the original model didn't look 'sufficiently professional' to be permitted in operating rooms. Finally, Dennis's appointment as department chairman was stalled by the executive faculty council for over a year, and he seriously considered returning to Minnesota.

While Dennis was struggling with the various obstacles at his new institution, F. John Lewis at the University of Minnesota performed the first successful open-heart surgery, using hypothermia, in 1952; Henry Swan at the University of Colorado, also working with hypothermia, did the first of a large series of successful heart operatons in January 1953; and John Gibbon in Philadelphia performed the first successful machine-supported open-heart surgery in April 1953. In 1954, C. Walton Lillehei began using cross-circulation (using a donor to pump and oxygenate the blood) to repair heart defects at the University of Minnesota. John Kirklin, using a modified Gibbon pump-oxygenator at the Mayo Clinic, did eight cardiac operations in early 1955, with four survivors. Dennis and his team were finally able to carry out their first successful operation, using their improved machine, on June 30, 1955. During the next five years they and other teams greatly improved the survival rates among their cardiac surgery cases, and the heart-lung machine technology continued to evolve. The oxygenator design that predominated for many years after 1960 was neither Gibbon's nor Dennis's, but the bubble oxygenator designed by another Minnesota researcher, Richard DeWall. In this and similar designs, oxygen was bubbled into the blood, and the bubbles removed by de-foaming silicone compounds, bubble traps, and filters before return to the patient.

During the next fifteen years, Dennis divided his time between his surgical research and his departmental duties. Like other mechanically-inclined cardiac surgeons (e.g., Adrian Kantrowitz and Michael DeBakey), he experimented with techniques and devices to aid adult patients with heart failure. One early effort involved using partial heart-lung bypass to take over for the left ventricle after a heart attack. On sabbatical in 1960-61, Dennis worked on this idea with Ake Senning and Clarence Crafoord at Sweden's Karolinska Institute; their clinical success rate was poor, but the studies generated much new information about how bypass affects the heart. For a time his team worked to develop synthetic heart valves (to replace those damaged by diseases such as rheumatic fever), and the technique of gas endarterectomy (for removing blockage in coronary arteries), among others. He also continued surgical studies of gastrointestinal conditions.

As department chair, Dennis had to recruit research-oriented faculty and staff to an institution that had no real research programs, and negotiate with Brooklyn hospitals for clinical resources for Downstate's surgical residents. He also sought to raise the professional standards at affiliated institutions, working to eliminate older practices such as fee-splitting (where surgeons gave a portion of their fees to the physicians who referred patients), which could compromise the residency program's accreditation. During these years, as his colleague Adrian Kantrowitz later recalled, Dennis provided crucial support to "a large group of talented young surgeons eager to push back the frontiers of cardiothoracic and vascular surgery. . . . He defied bureaucratic agendas and went to all practical lengths to ensure that those he trained or took into his department could continue to advance their innovative research."

Dennis was active in many professional groups, including the American College of Surgeons and the American Heart Association, which helped to shape research and regulatory guidelines for a rapidly expanding array of medical technologies that included pacemakers, cardiac assist devices, and renal dialysis machines, among others. Working with the National Society for Medical Research (NSMR), Dennis was also a key participant in the anti-vivisection debates of the mid-1960s. Animal rights lobbyists had proposed a bill--modeled on England's animal protection laws--to severely limit researchers' use of animals. While certainly not against humane treatment of animals, NSMR members strongly opposed the proposed government licensing of researchers and monitoring of individual projects, and successfully fought to reshape the legislation. The Animal Welfare Act of 1966 regulated the treatment of animals kept in research facilities and zoos, or transported by dealers. The law, amended 6 times between 1970 and 2007, imposes minimum standards of care, and limits on the use of animals. Researchers are required to use anesthesia or analgesia for painful procedures, consider alternatives to using animals, provide adequate exercise, and have their facilities supervised by qualified professionals. Dennis continued to be a staunch advocate of animal research, arguing that many twentieth century achievements in medicine would have been impossible without it.