Recently some studies have been carried out on RCCI (reactivity controlled compression ignition) engines; however, they routinely used the “one factor at a time” approach, which may neglect interactions among the manipulated factors. This paper reports the use of a more effective approach based on fractional factorial design to investigate the way that injection strategy might affect performance and emissions formation of such engines. In this work, six factors, namely the first SOI (start of injection) timing, the first ID (injection duration), the second SOI timing, the second ID, the diesel mass fraction in the first injection and the ratio of natural gas to total air, were considered. Sixteen simulated runs were conducted to evaluate the performance and emissions of an engine by using coupled KIVA4–CHEMKIN code with detailed reaction mechanism. The results show that premixed natural gas, which is the most dominant one, has a positive correlation with indicated power, and could reduce CO (Carbon Monoxide), NOx (Nitrogen Oxides) and soot emissions simultaneously. To further reduce NOx, both retarded second SOI timing and extended second ID are suggested. Finally, sequential studies are suggested to the direction with higher percentages of premixed low cetane number fuel.