Introduction: Pyoderma gangrenosum (PG) is a phenomenon of cutaneous ulceration with unknown etiology. About half the cases have associated extracutaneous manifestations or associated systemic diseases. The most commonly associated systemic disorders include inflammatory bowel disease (IBD), hematologic malignancies, autoimmune arthritis, and vasculitis. This is a case report about giant PG with ulcerative colitis (UC), which is extremely rare. Case Presentation: A 39-year-old female farmer with UC for the past 3 years presented with multiple painful ulcers, erosion, exudation, and crusting on the right leg for 1 month. A cutaneous examination showed diffusely distributed, multiple, well-defined, deep purulent ulcers on the right medial shank measuring 6 to 20 cm and sporadic worm-eaten ulceration on the right ectocnemial, with severe oozing and erosions. The ulcerations exhibited deep undermined borders, granulated tissue and a black eschar at the base. The right shank and feet were severely swollen, restricting movement. The arteria dorsalis pedis pulse was good, with normal sensation on the skin of the right shank and feet. Laboratory examinations showed a white cell count of 11.8 x 109/L, hemoglobin was 91 g/L, erythrocyte sedimentation rate was 82 mm/h, unelevated procalcitonin, serum C-reactive protein was 131.29 mg/L, and a negative tuberculin skin test. Enteroscopy demonstrated endoscopic evidence of UC. A skin lesion biopsy showed superficial erosion and scarring. Partial epidermal hyperplasia, partial epidermal atrophy and thinning, mild edema of the dermal papill. Most of the middle and lower part of the dermis, showed dense lymphocytes, histiocytes, multinucleated giant cells, and neutrophil infiltration. PG with UC was diagnosed based on clinical manifestations, laboratory examinations and enteroscopy results. Interventions: She was treated with topical applications of povidone iodine and kangfuxin solution twice daily, methylprednisolone sodium succinate 40 mg and compound glycyrrhizin 60 mg via intravenous drip once a day, along with thalidomide 50 mg twice daily. The UC was controlled with mesalazine. Outcomes: She required multiple therapies to achieve PG healing 3 months later. No PG recurrence was observed during the 1-year follow-up. Conclusion: Recognizing the clinical features of PG and its pathogenic nature, ensuring timely management fundamental for preventing severe destruction and deformity, and control of associated diseases are important aspects of treatment. Combination therapy is essential for PG patients with IBD.