In the present study, the effects of biodiesel-methanol blends on the performance and emissions of diesel engine at an altitude of 2400 m, were investigated experimentally and using response surface methodology (RSM). The RSM models were developed using experimental data. Methanol ratio, injection pressure (IP) and injection timing (IT) were selected as the input parameters, while power output, brake specific energy consumption (BSEC), nitrogen oxides (NOx) and smoke emissions were chosen as the response parameters. The desirability approach of the RSM was used to optimize the methanol ratio and injection system parameters for improved engine performance and lower emissions at high alitiude. The optimum values of input parameters were 95.27 MPa of IP, 15.13 BTDC of IT and 17.32 % methanol ratio, and the corresponding responses of power output, BSEC, NOx and smoke with a high desirability of 0.767 were 23.7 kW, 9.94 MJ/kWh, 7.08 g/kWh NOx and 0.020 g/kWh, respectively.