Persistent, chronic, relapsed, or refractory immune thrombocytopenia (ITP) remains difficult to manage. CD38 is highly expressed on plasmablasts and long-lived plasma cells, providing a rationale for CD38-targeted therapy. We conducted a PRISMA-guided systematic review and single-arm meta-analysis evaluating anti-CD38 monoclonal antibodies in adults with ITP (PROSPERO: CRD420261448457). Five studies involving 164 patients treated with CM313, daratumumab, or mezagitamab were included. The pooled overall response rate was 89.2% (95% CI: 78.8–99.5), platelet response ≥50 × 10⁹/L was 80.8%, and complete response was 65.1%. Rescue therapy was required in 25.9% (95% CI: 12.9–39.0). Any treatment-related adverse event occurred in 59.2% (95% CI: 45.2–73.2), upper respiratory tract infection in 16.9% (95% CI: 5.7–28.2), and grade ≥3 treatment-related adverse events in 4.6%. Anti-CD38 monoclonal antibodies demonstrated encouraging efficacy with infrequent severe treatment-related toxicity. Larger randomized trials are needed to confirm response durability and establish their position in the ITP treatment pathway.