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A female in her 30s from Missouri with no significant past medical history presented to the emergency department with worsening fatigue, haematuria and back pain following a brown recluse spider bite. On admission, laboratory findings were significant for anaemia, leukocytosis, hyperbilirubinaemia, elevated lactate dehydrogenase, low haptoglobin and a positive direct antiglobulin test. The working diagnosis was autoimmune haemolytic anaemia secondary to a brown recluse spider bite; a rare but serious haematologic complication associated with brown recluse spider bites. The patient required multiple red blood cell transfusions, high-dose corticosteroids and antibiotic therapy. Her condition improved with pharmacologic treatment, and she was discharged home with outpatient haematology follow-up. This case highlights the potential for systemic haemolysis in the setting of brown recluse spider bites and underscores the importance of early recognition and comprehensive management.