In recent decades, natural fibers reinforced composites in various applications have significantly developed. One of the critical properties of hybrid composites is their fatigue behavior, which affects the lifetime and application range of these materials, especially when the composite is drilled. This study aims to analyze the fatigue behavior of the central open-hole kenaf/glass multilayer hybrid composites. For this purpose, pure and hybrid kenaf/glass four layers composite samples with different stacking sequences, with and without a central hole were produced, and their tensile strength was evaluated. Afterward, the optimized hybrid composite (GKKG) and two pure glass (G4) and kenaf (K4) samples were analyzed under the fatigue tensile test at three stress levels. The results showed that the four layers drilled pure glass sample exhibited the highest fatigue strength, enduring 115,000 cycles at a stress level of 50%. The drilled hybrid kenaf/glass sample (GKKG) also showed outstanding fatigue strength, bearing approximately 54,000 cycles at a stress level of 50%. The slope of the stress-logarithm(N) curve of the hybrid sample was considerably smaller than the pure glass. This indicates lower sensitivity of drilled hybrid composites reinforced with natural fibers to the fatigue loading.