American football is the sport with the highest rates of concussion injuries. Biomedical engineering applications may support athletes in monitoring their injuries, evaluating the effectiveness of their equipment, and leading industrial research in this sport. This literature review aims to report on the applications of biomedical engineering research in American football, highlighting the main trends and gaps. The review followed the PRISMA guidelines and gathered a total of 1629 records from PubMed (n = 368), Web of Science (n = 665), and Scopus (n = 596). The records were analyzed, tabulated, and clustered in topics. In total, 112 studies were selected and divided by topic in the biomechanics of concussion (n = 55), biomechanics of footwear (n = 6), biomechanics of sport-related movements (n = 6), the aerodynamics of football and catch (n = 3), injury prediction (n = 8), heat monitoring of physiological parameters (n = 8), and monitoring of the training load (n = 25). The safety of players has fueled most of the research that has led to innovations in helmet and footwear design, as well as improvements in the understanding and prevention of injuries and heat monitoring. The other important motivator for research is the improvement of performance, which has led to the monitoring of training loads and catches, and studies on the aerodynamics of football. The main gaps found in the literature were regarding the monitoring of internal loads and the innovation of shoulder pads.