Daptomycin (DAP) is a cyclic lipopeptide antibiotic with bactericidal activity against gram-positive bacteria. The most common adverse reaction is myotoxicity characterized by rhabdomyolysis. Other reported adverse reactions include gastrointestinal symptoms, skin lesions, bleeding, and pulmonary involvement. Neurotoxicity is rare and its mechanism remains partially elucidated. We report a case of confusion consistent with DAP-induced neurotoxicity. A 73-year-old obese man was treated with DAP 9 mg/kg for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia associated with foot osteitis and cervical posterior inter-apophyseal arthritis. On the fifth day of treatment, he developed spatial disorientation, and serum DAP concentrations were very high. DAP-induced neurotoxicity was suggested. His neurological status returned to normal after treatment was stopped. This observation describes a relationship between confusion and DAP that is favored by obesity. Clinicians should be alert for neurologic disorders associated with DAP. It is prudent to reduce doses in obese patients.