In the present study, performance of an HCCI engine powered with ethanol/toluene/n-heptane tri-fuel blend was optimized by using response surface method. The studied independent parameters were engine speed, lambda ratio, and fuel blends. The impact of these parameters on engine torque, COVimep, CA10, CA50, indicated thermal efficiency, IMEP along with emissions of NOX, CO, and HC comprehensively investigated. According to the results, the optimal HCCI engine operation condition was proposed as engine speed of 1343 rpm, lambda value of 2.29, and ethanol ratio of 22%. At this condition, the engine outputs, i.e., IMEP, COVimep, indicated thermal efficiency, CA10, and CA50, engine torque were estimated to be 4.21 bar, 4.28%, 0.37, 1.41 °CA, 4.62 °CA, and 8.2 Nm, respectively. The engine-out emissions, including HC, NOX, and CO emission, were predicted to be 243 ppm, 1.05 ppm, and 0.03%, respectively. The result indicates that using ethanol/toluene/n-heptane fuel mixture improved the HCCI combustion and NOX emission. The near-zero NOX emissions were recorded at all fuel mixture. However, enhancing ethanol ratio in the fuel blends showed an increase in CO and HC emissions. Overall, this study showed that response surface technique could be used as a promising method to model the HCCI engines.