This study aimed to investigate the role of myosteatosis, sarcopenia, and perioperative serum biomarkers as independent predictors of major complications within 180 days following radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). We retrospectively analyzed of 127 MIBC patients who underwent RC between 2013 and 2023 at a single institution. Preoperative body composition was assessed using CT scans at the L3 vertebral level to measure psoas muscle density (PMD), skeletal muscle density (SMD), axial muscle density (AMD), and muscle indices. Novel inflammatory and nutritional markers, including serum chloride levels within 24 h post-surgery, were also evaluated. Major complications were defined as Clavien-Dindo grade ≥ 3. Multivariate analysis was performed to identify independent predictors of postoperative complications. Among the cohort, 30.7% of patients experienced major complications within 90 days, and 36.2% within 180 days. Sepsis was the most common major complication (19 of 241 complications, 7.9%). Ten patients died during the observation period. Myosteatosis (p = 0.002) and postoperative serum chloride levels (p < 0.001) were significant independent predictors of 180-day major complications. Patients with low PMD had an adjusted odds ratio (OR) of 3.959 for developing major complications, while increased serum chloride levels were associated with a reduced risk of complications (OR = 0.985). Multivariate analysis reveals associations between myosteatosis, aging, and anemia. Myosteatosis and perioperative serum chloride levels are significant predictors of major complications after RC for MIBC. Incorporating body composition analysis and early serum chloride monitoring into perioperative care may improve risk stratification and patient outcomes following RC.