Background: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is a recognized complication, often attributed to mechanical trauma, chemical injury, or bacterial contamination by enteric pathogens such as Escherichia coli, Enterococcus, and Klebsiella. However, Staphylococcus aureus has not been previously reported as a causative agent of PEP. Case presentation: We present a case series of two young female patients who developed severe necrotizing PEP associated with S. aureus following ERCP. Both cases were characterized by prolonged hospitalizations, multiple interventions, and a complicated clinical course. The first patient, a 26-year-old female, developed methicillin-resistant Staphylococcus aureus (MRSA) PEP, requiring serial percutaneous drainage and pancreatic necrosectomy. She was treated with intravenous daptomycin followed by long-term oral doxycycline. The second patient, a 22-year-old female, developed methicillin-susceptible Staphylococcus aureus (MSSA) PEP complicated by persistent peripancreatic abscesses, necessitating multiple necrosectomy procedures and extended antibiotic therapy with cefazolin, dalbavancin, and cephalexin. Conclusion: This case series represents the first documented instances of S. aureus associated PEP. These cases highlight the potential for S. aureus as a post-ERCP pathogen and underscore the importance of considering non-enteric bacteria in PEP patients with an unexplained infectious course. Management requires a multidisciplinary approach, with emphasis on source control and selection of antibiotics with adequate pancreatic penetration. Further research is needed to better characterize the pathophysiology and optimal treatment of S. aureus-associated PEP.