Introduction: The aim of the study was to analyze risk factors for hematoma expansion (HE) in patients undergoing decompressive hemicraniectomy (DC) in patients with elevated intracranial pressure due to spontaneous intracerebral hematoma (ICH). Methods: We retrospectively evaluated 72 patients with spontaneous ICH who underwent DC at our institution. We compared the pre- and postoperative volumes of ICH and divided the patients into two groups: first, patients with postoperative HE > 6 cm3 (group 1), and second, patients without HE (group 2). Additionally, we screened the medical history for anticoagulant and antiplatelet medication (AC/AP), bleeding-related comorbidities, age, admission Glasgow coma scale and laboratory parameters. Results: The rate of AC/AP medication was higher in group 1 versus group 2 (15/16 vs. 5/38, p < 0.00001), and patients were significantly older in group 1 versus group 2 (65.1 ± 16.2 years vs. 54.4 ± 14.3 years, p = 0.02). Furthermore, preoperative laboratory tests showed lower rates of hematocrit (34.1 ± 5.4% vs. 38.1 ± 5.1%, p = 0.01) and hemoglobin (11.5 ± 1.6 g/dL vs. 13.13 ± 1.8 g/dL, p = 0.0028) in group 1 versus group 2. In multivariate analysis, the history of AC/AP medication was the only independent predictor of HE (p < 0.0001, OR 0.015, CI 95% 0.001–0.153). Conclusion: We presented a comprehensive evaluation of risk factors for hematoma epansion by patients undergoing DC due to ICH.