Septic arthritis (SA) is a less common joint pathology with potentially fatal outcome. It is considered a medical emergency, in which prompt diagnosis and differentiation of bacterial etiology is essential for appropriate management. The knee is the most prevalent site for SA (~50% of cases), followed by hip, shoulder, and elbow. Early intervention requires an accurate diagnosis and imaging techniques enable both a positive diagnosis, as well as arthrocentesis and liquid analysis, the "gold standard" criteria. We report the case of a 70-year-old patient, with history of rheumatoid arthritis (RA), diabetes mellitus (DM) and persistent left malum perforans in the last year, with development of a severe and debilitating Staphylococcus aureus-related SA of the left ankle, which posed significant therapeutic challenges. He developed a plantar lesion at the ball of the left foot, in the past one year, which was labeled as malum perforans in the setting of DM. Musculoskeletal ultrasound was the primary imaging technique used to define the location and extent of the infectious process. Cultures drawn from the tissue were positive for S. aureus. After an antibiotic course, the apparent infectious features were remitted but the long-lasting open wound failed to improve. Antibiotic therapy was initiated in accordance with culture sensibility tests but short- and long-term outcome was unfavorable with both treatment unresponsiveness and comorbidity burden posing considerable difficulties. The association and interrelation between different comorbidities (such as hypertension, diabetes, or obesity), chronic systemic inflammation (e.g., C-reactive protein level, disease activity), and RA medication is sometimes difficult to understand and to address in daily practice, and this case report highlights multiple toils encountered in a SA patient with RA on immunosuppressive therapy and complicated DM.