Rifampin-induced acute kidney injury is very rare. Most cases of acute renal injury from rifampin use are related to acute tubular necrosis and acute interstitial nephritis. In this case report, we detail a unique presentation of rifampin-associated acute intravascular hemolysis and subsequent tubular injury in a tuberculosis patient. The patient had presented to the hospital with acute kidney injury and oliguria from intravascular volume depletion secondary to intractable vomiting. The patient had stopped taking his antituberculosis medications two weeks before hospitalization. At the time of hospital admission, his antituberculosis regimen of rifampin and isoniazid was reinstituted. Within four days of initiation of rifampin, he developed acute hemolytic anemia. His kidney biopsy revealed hemoglobin pigment deposition in the kidney tubules. Rifampin was discontinued, and he received a total of eight hemodialysis treatments spanning over 17 days. Subsequently, after discontinuing rifampin, his anemia and oliguria resolved with renal function markedly improved to near normal baseline levels. This case report also offers a review of known mechanisms of rifampin-induced acute hemolysis and acute renal failure, along with a discussion of contemporary literature.