BACKGROUND A recently described zoonotic viral infection, mpox (monkeypox), is an Orthopoxvirus transmitted by close contact, which causes symptoms similar to smallpox, although less severe. This report presents the case of a 40-year-old man with anemia, proctitis, rectal bleeding, and a perianal rash due to mpox infection. CASE REPORT A 40-year-old man with a medical history of human immunodeficiency virus (HIV) and syphilis presented multiple times with progressive and painful perianal lesions. On initial presentation, swabbing of the lesions and polymerase chain reaction (PCR) testing confirmed a diagnosis of mpox infection, and treatment with a 14-day course of Tecovirimat was started. Nine days after initiating Tecovirimat, the patient presented again with worsening perianal pain and associated hematochezia resulting in acute symptomatic anemia. Despite a blood transfusion to treat his anemia, the patient's status declined as his viral symptoms progressed. Computed tomography (CT) investigation demonstrated significant proctitis with interval development of small perianal abscesses. A multidisciplinary approach for medical management and treatment was instituted. The resolution of the patient's anemia and mpox proctitis was confirmed on follow-up. CONCLUSIONS Despite treatment with antiviral agents, mpox infection can progress quickly; thus, swift management with a multidisciplinary approach and close follow-up is needed to treat and prevent secondary complications such as anemia and proctitis. Further data collection regarding the sexual practices of those with diagnoses of mpox as well as seminal, anorectal, and genital swabbing would be valuable to confirm the mode of transmission and cause of mpox proctitis.