Introduction: Pyoderma gangrenosum (PG) poses a significant dermatological challenge due to its rapidly evolving, painful, necrotic ulcerations. Understanding its multifaceted pathogenesis and diverse clinical presentation is crucial for effective management. Objectives: We aimed to analyze demographic characteristics, clinical manifestations, lesion distributions, systemic disease associations, therapeutic interventions, and patient outcomes in PG cases. Methods: Medical records from 2017 to 2023 of PG patients at IRCCS Sant’Orsola Malpighi Hospital, Bologna, Italy, were retrospectively analyzed. Inclusion criteria encompassed persistent ulcers with clinical and histological evidence of PG, excluding cases with alternative diagnoses or inadequate follow-up. Clinical evaluations, including pain assessment and lesion measurements, were conducted at diagnosis and follow-up visits. Results: A total of 44 patients were evaluated. Pain was a universal symptom, and tissue pathergy was documented in 28.6% of patients. Ulcerative PG was the most common subtype (88.1%). Associations with inflammatory bowel diseases (25%), rheumatoid arthritis (9.1%), and hematological diseases (17.2%) were noted. Lower limbs were frequently affected (63.6%). Treatment approaches included wound management, topical and systemic corticosteroids, and immunosuppressive therapy, with varying response rates. Conclusion: Advanced dressing and steroid therapy were pivotal in mild PG cases, while moderate to severe cases often associated with systemic diseases showed incomplete healing despite treatment, especially in patients with inflammatory bowel diseases and hematological disorders. This study contributes to understanding PG's complexities, highlighting the need for multidisciplinary management and further prospective research.