Tumor lysis syndrome (TLS) is a life-threatening condition due to malignant tumor cell lysis resulting in severe metabolic derangements that require prompt recognition and management to prevent progression to end-organ damage and death. This case describes a patient presenting with clinical and laboratory abnormalities complicated by multi-organ dysfunction concerning spontaneous TLS from a suspected undiagnosed malignancy. The patient had an unremarkable malignancy workup and was ultimately diagnosed with endocarditis, which improved with treatment of the infection. Therefore, this case demonstrates that systemic infections may rarely present with metabolic abnormalities and multi-organ dysfunction resembling spontaneous TLS.