Summary Background Pyoderma gangrenosum (PG) is a neutrophilic dermatosis with substantial morbidity. There is no consensus on gold‐standard treatments. Objectives To review the effectiveness of systemic therapy for PG. Methods We searched six databases for 24 systemic therapies for PG. Primary outcomes were complete healing and clinical improvement; secondary outcomes were time to healing and adverse effects. Results We found 3326 citations and 375 articles underwent full‐text review; 41 studies met the inclusion criteria. There were 704 participants in 26 retrospective cohort studies, three prospective cohort studies, seven case series, one case–control study, two open‐label trials and two randomized controlled trials (RCTs). Systemic corticosteroids were the most studied (32 studies), followed by ciclosporin (21 studies), biologics (16 studies) and oral dapsone (11 studies). One RCT (STOP‐GAP, n = 121) showed that prednisolone and ciclosporin were similar: 15–20% of patients showed complete healing at 6 weeks and 47% at 6 months. Another RCT (n = 30) found that infliximab was superior to placebo at 2 weeks (46% vs. 6% response), with a 21% complete healing rate at 6 weeks. Two uncontrolled trials showed 60% and 37% healing within 4 months for canakinumab and infliximab, respectively; other data suggest that patients with concurrent inflammatory bowel disease may benefit from biologics. The remaining studies were poor quality and had small sample sizes but supported the use of corticosteroids, ciclosporin and biologics. Conclusions Systemic corticosteroids, ciclosporin, infliximab and canakinumab had the most evidence in treating PG. However, current literature is limited to small and lower‐quality studies with substantial heterogeneity. What's already known about this topic? Pyoderma gangrenosum (PG) is a neutrophilic dermatosis with substantial morbidity that can be managed with multiple systemic agents. However, there is no consensus on the most effective therapy. What does this study add? Systemic corticosteroids, ciclosporin, infliximab and canakinumab had the strongest evidence in treating PG, although, overall, there are few high‐quality studies. Despite showing promise, systemic therapies appear to have high rates of nonresponse or recurrence; future studies should explore the effectiveness of combinations of topical and systemic agents Linked Comment: Thomas. Br J Dermatol 2018; 179:240–241. Plain language summary available online