Background: Post-mastectomy complications remain a major concern in patients with advanced breast cancer, particularly in low-resource settings where delayed diagnosis and advanced-stage presentation are common. This study aimed to identify factors associated with post-mastectomy complications among patients with advanced breast cancer in Douala, Cameroon. Methods: A multicenter cross-sectional analytical study was conducted in four reference hospitals in Douala from January 1, 2014, to December 31, 2023. A total of 523 patients who underwent mastectomy for histologically confirmed breast cancer were included. Sociodemographic, clinical, paraclinical, therapeutic, and postoperative data were collected using a structured form. Bivariate and multivariate logistic regression analyses were performed using SPSS software version 28.0. Statistical significance was set at p < 0.05. Results: The mean age of the patients was 47.0 ± 12.1 years. The most frequent post-mastectomy complications were lymphedema, anxiety, seroma, depression, pain, surgical site infection, sexual dysfunction, sensory disturbance of the arm, hemorrhage, and hematoma. In multivariate analysis, age 65–75 years, consultation delay of 6–9 months, invasive lobular carcinoma, and stage IIIb disease remained independently associated with post-mastectomy complications, whereas surgeon specialty lost statistical significance after adjustment. Conclusion: Advanced age, delayed consultation, invasive lobular carcinoma, and stage IIIb breast cancer were associated with post-mastectomy complications. Early diagnosis, timely surgical management, and multidisciplinary perioperative care may reduce postoperative morbidity and improve outcomes among patients with advanced breast cancer in Cameroon.