Dr. Kelly obtained his medical degree from the University of Illinois College of Medicine in Chicago in 1982. He was an Intern (1982-1983) and an Assistant Resident in Medicine (1983-1985) at Barnes Hospital in St. Louis. Thereafter, he did a Postdoctoral Research Fellowship in the Department of Biological Chemistry (1985-1987) followed by Clinical Cardiology Fellowship training (1987-1989) at Washington University School of Medicine. Dr. Kelly joined the Washington University School of Medicine faculty in 1989 and rapidly moved up the ranks to Professor of Medicine, Molecular Biology & Pharmacology, and Pediatrics (1999). While at Washington University School of Medicine, Dr. Kelly held the Tobias and Hortense Lewin Professorship and served as Chief of the Cardiovascular Division (2006-2008). He launched the Center for Cardiovascular Research at Washington University in 1996. In 2008, Dr. Kelly assumed the role of founding Scientific Director for Sanford Burnham Prebys Medical Discovery Institute located in Lake Nona, Florida. In August 2017, he moved to the University of Pennsylvania where he was named Director of the Penn Cardiovascular Institute.

Dr. Kelly's research interests stem from an early fascination with rare inborn errors in mitochondrial metabolism in children which cause sudden death and heart failure. As a young researcher at Washington University, Dr. Kelly defined the genetic basis for a common inborn error in mitochondrial fatty acid oxidation, work that led to the development of practical screening tests for newborns. Thereafter, he became interested in how similar derangements in cardiac energy metabolism contribute to heart failure and sudden death in common acquired forms of mitochondrial diseases caused by hypertension, ischemic injury, and diabetes. His work defined the transcriptional regulatory axis involved in the control of cardiac fuel and energy metabolism through pioneering fundamental work on nuclear receptors including the PPARs, estrogen-related receptors (ERRs), and their transcriptional coactivator PGC-1. The Kelly laboratory has identified molecular "switches" in this regulatory pathway that potentially define distinct forms of heart failure, an important step towards identifying therapeutic targets for phenotype-specific treatment of heart failure. More recently, the Kelly laboratory has applied proteomic and metabolomic approaches to investigating the metabolic origins of heart failure.

Dr. Kelly has made significant contributions to biomedical research beyond his discoveries. He is an Associate Editor for The Journal of Clinical Investigation and the Journal of the American College of Cardiology-Basic to Translational Science. He serves, or has served, on the Editorial Boards of Genes & Development, Nuclear Receptor Signaling, Circulation, and Circulation Research. He has held leadership advisory roles for the American Heart Association (AHA), the National Heart, Lung, and Blood Institute, Pfizer and Eli Lilly. Dr. Kelly is a member of the American Society for Clinical Investigation, the American Association of Physicians, and is a recipient of the AHA Basic Research Prize.