The objective of this study is to use response surface methodology to forecast the performance, combustion, and emission characteristics of an advanced injection strategy-assisted diesel engine running on waste frying oil methyl ester. The experiment was carried out on a diesel engine using a high-pressure fuel injection system. The main injection timing ranges varied from 16 to 24 °CA bTDC, whereas the post-injection ranges from −6 °CA bTDC to 6 °CA aTDC. The injection quantity for the main and post injections quantity varied from 70 % to 90 %, 10 % to 30 %, and the injection pressure is set at 500 bar. Experiments were carried out using a design matrix developed by the design of experiments. At 100 % load, B100-90 %-10 % obtained the highest BTE of 33.87 % and the lowest fuel consumption of 0.268 kg/kW-hr. At the main injection timing of 22 °CA and post-injection timing of −4 °CA, D100-80 %-20 % achieved the lowest unburned hydrocarbon, Smoke emission of 13 ppm, and 1.613 FSN respectively. The point prediction approach was used to forecast the combustion and emission parameters of a diesel engine, and the predicted results were in good agreement with the experimental results. Furthermore, when compared to advance injection timing for biodiesel fuel, retarded injection timing reduces nitric oxide emission. The Split injection strategy is one of the most effective techniques to reduce soot and NO × emissions while maintaining diesel engine efficiency.