We report a case of a high-performance athlete with hemoglobin SC who presented with asymmetric calf soreness after an intense calf workout. By ultrasonography, he was diagnosed with a deep vein thrombosis (DVT) of his right calf. Subsequently he presented with a number of sequelae of sickle cell disease: acute chest syndrome, avascular necrosis of the hips, and chronic kidney disease. The case is instructive as an example of DVT after exercise of the lower extremities, which has not been documented well. The case also illustrates a number of health sequelae of sickle cell disease that mimic more common musculoskeletal complaints. Sports medicine providers will have to consider these uncommon but profound diagnostic entities when caring for athletes with sickle cell disease. The case further highlights how research can inform the clinical decisions and policies aimed at reducing the risk of life-threatening and lifelong sequelae of sickle cell disease in athletes.