OBJECTIVE To design and synthesize trifluoromethoxy chalcone derivatives based on the natural licorice chalcone parent as the lead compound backbone, and to study their anti-cervical cancer activity in vitro. METHODS New trifluoromethoxy chalcone derivatives were synthesized by Claisen-Schmidt aldol condensation. The structures were confirmed by ¹H-NMR, ¹³C-NMR and HR-ESI-MS. The cytotoxic activity of the target compounds on cervical cancer cell lines HeLa, SiHa, C-33A and normal cervical epithelial immortalized H8 cells were determined by MTT assay, and the structure activity relationship (SAR) was analyzed and the candidate compounds were selected. The effects of candidate compound 3o on invasion, migration, apoptosis and cell cycle of HeLa cells were determined by Transwell and flow cytometry. The candidate compound 3o was docked to the MDM2 and protein target by molecular docking method, and the binding ability and binding characteristics of the compound to the target protein molecules were determined. The regulatory effects of the candidate compounds on MDM2 and p53 proteins were assessed using Western Blot analysis. RESULTS Twenty new trifluoromethoxy chalcones were synthesized. Candidate compound 3o showed the strongest inhibitory activity against cervical cancer cells (IC₅₀=4.60±0.40 μmol·L^-1), which was significantly better than that of positive drug cisplatin (IC₅₀=17.16±0.93 μmol·L^-1). The candidate compound 3o could effectively inhibit the invasion and migration of HeLa cells, induce apoptosis and arrest the cell cycle at G₀/G₁ phase. Candidate compound 3o binds to key amino acids in p53 binding pocket of MDM2 protein (binding energy -37.62 kcal·mol^-1). The compounds significantly downregulated MDM2 protein expression while upregulating p53 protein levels. CONCLUSION The research results provide experimental evidence for screening new chalcone derivatives as targeted, effective, and low-toxicity anti-tumor candidates against cervical cancer.