Background/Objectives: Myeloid sarcoma (MS) is a rare extramedullary manifestation of myeloid blasts, with limited systematic data, particularly regarding molecular (NGS) concordance between MS tissue and bone marrow. We hypothesized that clonal heterogeneity may exist between these sites due to their distinct biological environments. Methods: We conducted a systematic review and meta-analysis of 85 studies encompassing 7241 MS patients, to evaluate clinical characteristics, mutational profiles, treatment patterns, and outcomes. Mutational concordance or discordance between MS and bone marrow was assessed in a subset of 112 patients. Results: Male predominance (59%) and skin/soft tissue localization (31%) were most common. NPM1 (25%) and FLT3 (20%) were the most frequently reported mutations. Among 112 patients with paired sequencing, 56% showed discordance in mutational profiles. NPM1 was significantly enriched in MS sites compared to bone marrow (35% vs. 21%, p = 0.02) and was associated with skin involvement. Discordance was more frequent in isolated and secondary MS. Venetoclax with hypomethylating agents achieved a 44% response rate, mainly in secondary MS. Post-transplant isolated extramedullary relapse occurred in 46% of relapsed patients and was linked to high rates of graft-versus-host disease. The pooled median overall survival was 12.8 months. Conclusions: MS demonstrates significant molecular heterogeneity. Routine site-specific NGS profiling may guide targeted therapy in this rare disease.