Aspirin resistance (AR) commonly refers to the concept of reduced aspirin efficacy in preventing cardiovascular disease and platelet inhibition. Obesity increases the risk of heart disease three- to four-fold and has been associated with AR. Aspirin is used as a tool for both primary and secondary prevention, but recent studies suggest that its lack of efficacy for primary prevention is partly attributable to obesity. Several mechanisms have been described that contribute to AR in obese patients using pharmacokinetics and pharmacodynamics. AR may be attenuated through weight loss, alternative dosing regimens, and different drug formulations. With the global rise of obesity, it is imperative to find preventive therapies that adequately address atherosclerotic cardiovascular disease (ASCVD) risk in this population.