Denosumab has transformed the management of giant cell tumor of bone (GCTB), particularly in cases that are unresectable or surgically morbid. However, accumulating reports of malignant transformation (MT) during or after therapy have raised concern about a potential causal association. We conducted a systematic review and meta-analysis to estimate the incidence of MT in denosumab-treated GCTB and to characterize the clinical, radiological, and pathological features of affected patients. We searched PubMed/MEDLINE, Scopus, and Web of Science to October 2025 for studies reporting denosumab-treated GCTB with MT. Clinical trials, cohort studies, case series, and case reports with original patient data were eligible. Two reviewers independently performed study selection, data extraction, and risk-of-bias assessment. A random-effects meta-analysis was used to pool MT incidence. Twenty-four studies were included in the qualitative analysis, and 11 (800 denosumab-treated patients) contributed to the meta-analysis. MT was reported in 18 patients. The pooled incidence of MT was 3% (95% CI 2–7%; I2 = 49.2%). Patients who transformed typically had high-risk disease, characterized by axial or otherwise surgically challenging sites, multiple prior local procedures, recurrent disease, or previous radiotherapy. Among cases with available timing data, MT was diagnosed from 3 months to 6 years after denosumab initiation, although most transformations occurred during active treatment or within 1–3 years of treatment initiation. MT most often manifested as high-grade osteosarcoma or undifferentiated pleomorphic sarcoma, characterized by biphasic histology, a markedly increased Ki-67 index, and variable H3F3A status. The prognosis was poor despite aggressive multimodal treatment. Cohort studies were generally rated as fair to good quality, whereas non-randomized interventional studies had a serious to critical risk of bias. MT in denosumab-treated GCTB is rare and does not appear more frequent than historical baseline rates, but it predominantly affects a biologically and clinically high-risk subgroup. Vigilant clinical and radiological surveillance, prompt re-biopsy of atypical lesions, and referral to expert sarcoma centers are essential, and prospective registries with integrated molecular profiling are urgently needed.