Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare auto-inflammatory condition involving cutaneous and osteoarticular manifestations. This study presents a case where a 16-year-old male with glucose-6-phosphate dehydrogenase (G6PD) deficiency presented with severe nodulocystic acne after three weeks of isotretinoin therapy. In addition to worsening acne, the patient had bone and joint pain with movement restriction. The patient's workup showed elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), bilateral symmetrical sacroiliitis on magnetic resonance imaging (MRI), and multiple bony lesions on bone scintigraphy. A diagnosis of SAPHO syndrome possibly induced by isotretinoin was made. Isotretinoin discontinuation, analgesia, topical acne medications, prednisolone, and adalimumab yielded considerable clinical improvement.