The effect of water-soluble polymers (polyvinyl alcohol (PVA), polyacrylamide (PAM)) and chemical additives (silicone defoamer (SD), polycarboxylate superplasticizer (PC)), on the development of the strength of mortar was investigated using the BoxBehnken design (BBD). Quadratic equations were obtained for the correlation between dosages of chemicals and the strength of the mortar, and the order of the effectiveness of the chemicals was validated in Pareto charts with contour plots to illustrate the chemicals and their interactions on the strength enhancement of mortar. The results showed that the interaction effects of SD and PAM enhanced the strength of cement mortar for all curing times, and the rates of contribution were 16.5%, 20.1%, and 19.4%, respectively. On the basis of the performance analysis of the four additives, optimized formulations were highlighted via overlapped contour plots. Heat of hydration and scanning electron microscope (SEM) images were introduced to confirm the interaction between SD and PAM. The improvement of compressive strength attributes to the synergistic interactions between SD and PAM, including the physical interaction resulted from the doping of SD, which promoting the damage of air bubble, decreasing the porosity and increasing the compressive strength, and the chemical interaction resulted from the doping of PAM, which producing ionic compounds and forming dense structure.