Purpose To systematically evaluate the clinical efficacy and safety of antibiotic-loaded calcium sulfate (ALCS) as a local antibiotic delivery system for the treatment of osteomyelitis in adult patients, and to quantitatively synthesize the available evidence on infection eradication rate, bone healing rate, and complications through meta-analysis.Methods A systematic literature search was conducted across PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science from inception to December 2025, following the PRISMA 2020 reporting guidelines. Studies involving adult patients (≥ 18 years) with a confirmed diagnosis of osteomyelitis treated with ALCS as a local antibiotic carrier and reporting at least one clinical outcome measure were included. Single-arm proportions were pooled using the Freeman–Tukey double arcsine transformation and the DerSimonian–Laird random-effects model. Heterogeneity was assessed using the I² statistic and Cochran's Q test. Pre-specified subgroup analyses and leave-one-out sensitivity analyses were performed.Results Twenty-one studies comprising 1,461 patients were included. The pooled infection eradication rate was 87.2% (95% CI: 83.8%–90.3%, I² = 67.4%). The pooled bone healing rate was 78.0% (95% CI: 73.1%–82.5%, I² = 57.1%). Regarding complications, the wound drainage rate was 14.8% (95% CI: 11.3%–18.7%), the reoperation rate was 12.3% (95% CI: 8.0%–17.3%), and the amputation rate was 1.8% (95% CI: 0.7%–3.3%). Subgroup analysis revealed higher eradication rates in non-diabetic foot osteomyelitis (DFO) studies (88.2%) compared with DFO studies (79.1%). Sensitivity analysis demonstrated high robustness (86.2%–88.2%). Egger's test revealed no significant publication bias (p = 0.877).Conclusion ALCS demonstrates favorable efficacy in the treatment of osteomyelitis, with an infection eradication rate of approximately 87% and a bone healing rate of 78%. Wound drainage is the most common complication (14.8%), while the amputation rate remains low (1.8%). These findings support the use of ALCS as an effective and safe local antibiotic delivery system in the multidisciplinary management of osteomyelitis. However, the predominance of retrospective evidence and moderate-to-substantial heterogeneity indicate that well-designed randomized controlled trials are warranted to provide definitive evidence.Level of evidence Systematic review and metaanalysis, Level IV.