This paper reports the partial replacement of Portland cement (PC) by combination of metakaolin (MK) and nanoclay (NC) in sisal fiber-reinforced cement composites by studying the microstructure, mechanical behavior, and the interfacial properties between fiber and cement matrices. The mechanical properties of cement matrix and natural fiber-reinforced composites are studied using compressive strength development and flexural behavior, respectively. The tensile behavior of the natural fiber was also investigated and analyzed by Weibull distribution model. The characteristics of hydration products were analyzed by scanning electron microscope, X-ray diffraction, and thermogravimetry analysis. Our results show that the combination of MK and NC can improve the hydration of cement more effectively, with better microstructure and enhanced mechanical properties, than mixes without them. The calcium hydroxide (CH) contents of matrixes with 50 wt% combined substitutions, containing 1, 3, and 5 wt% of nanoclay, were 58.12, 60.16, and 64.25 % less than that of PC, respectively. The ettringite phase is also effectively removed due to the substitution of MK and NC, which improve both Al/Ca and Si/Ca ratios of calcium silicate hydrates (C-S-H) due to the high content of SiO2 and Al2O3. The interfacial bond between fiber and cement matrix and flexural properties of sisal fiber-reinforced cement composites are also significantly improved. The optimum interface adhesion between sisal fiber and matrix was achieved by replacing cement by 27 % MK and 3 % NC, which increased the bond strength and pull-out energy by 131.46 and 196.35 %, respectively.