Background Neoadjuvant therapy is increasingly used in the first-line setting in people with advanced endometrial cancer despite a paucity of evidence for this approach. Objective To systematically evaluate the literature in this area. Search Strategy Electronic searches of Ovid MEDLINE, Ovid Embase, Clinical trials.gov and the International clinical trials registry platform were performed for studies published between 1990 and 2021 comparing neoadjuvant therapy with upfront debulking surgery in Stage 3 or 4 endometrial cancers. Selection Criteria Studies reporting overall survival, progression free survival, adverse events and/or quality of life in those undergoing neoadjuvant therapy or upfront debulking. Data Collection and Analysis Odds ratios (OR) and log hazard ratios (HR) along with 95% confidence intervals (CI) were calculated and pooled for analysis. Risk of bias was assessed using the ROBINS-I tool. Main Results Eight non-randomised studies with a total of 50,510 patients were identified. These showed that patients undergoing primary chemotherapy had similar survival outcomes to those undergoing primary surgery (HR 1.26 (95% CI 0.95-1.69)). Fewer patients in the neoadjuvant group had surgery but those that did were less likely to be suboptimally cytoreduced (OR 0.24; 95% CI 0.21-0.28). Surgical morbidity was no different between the two approaches (OR 0.51, 95% confidence interval 0.08-3.25). However, the potential for bias in these studies is very high. Conclusion There is significant uncertainty as to whether the outcomes for those undergoing primary cytoreductive surgery or neoadjuvant chemotherapy in the presence of unresectable disease are better. Prospective reporting of outcomes is needed.