Professor Hennekens was the first John Snow Professor of Medicine as well as the first Eugene Braunwald Professor of Medicine at Harvard Medical School, and first Chief of Preventive Medicine at Brigham and Women's Hospital in Boston, MA. He is the first Sir Richard Doll Research Professor of Biomedical Science at Florida Atlantic University in Boca Raton, FL. Sir Richard was the Regius Professor of Medicine at the University of Oxford, and the first to demonstrate the association between cigarette smoking and lung cancer. Sir Richard Doll was a mentor, colleague, and friend of Professor Hennekens who spent a sabbatical year at Oxford where he was the first Project Director of the British Doctor's Trial of aspirin.

From 1995-2005 he was the 3rd most widely cited medical researcher in the world. In addition, 5 of the top 20 were his former fellows and/or trainees. His primary research focuses on the treatment and prevention of cardiovascular disease.

Professor Hennekens has devoted substantial time and effort to the elucidation of the benefits and risks of aspirin in the treatment and prevention of cardiovascular disease. Specifically, he was Principal Investigator of the Physician's Health Study, a trial funded by the National Institutes of Health which was the first to demonstrate that aspirin prevents a first heart attack. He was the US Principal Investigator for the Second International Study of Infarct Survival demonstrating that aspirin given within 24 hours of a suspected heart attack reduces subsequent heart attack, stroke, and vascular death. He was also a founding collaborator of the Antiplatelet Trialist's Collaboration demonstrating the clear benefits of aspirin among a wide range of survivors of prior occlusive vascular events.

Professor Hennekens currently is a part-time Special Government Employee serving as consultant to the Division of CardioRenal Drugs of the US Food and Drug Administration (FDA). He has served on FDA advisory panels for statins as well as selective cyclooxygenase-2 inhibitors and non-selective nonsteroidal anti-inflammatory drugs.