The aim of this study was to determine the effect on the flexural strength of the self-cured acrylic resin by incorporating short E-glass fiber (SEGF) and ultra-high-molecular-weight polyethylene (UHMW-PE) filler in the acrylic resin. Fifty-six rectangular (64 × 10 × 3.3 mm3) (ISO standard 20795-1:2013) self-cured acrylic resin specimens were fabricated and divided into seven groups per test, according to the percent by weight of SEGF and UHMW-PE filler (n = 8). Each testing group entails a control group and an addition of 1% and 2% SEGF, 1% and 2% UHMW-PE, 0.5% SEGF/UHMW-PE, and 1% SEGF/UHMW-PE. A three-point bending test was conducted to obtain the flexural strength of each specimen. The fractured surfaces of the specimens were evaluated, and a scanning electron microscope view was taken. Test results were statistically analyzed with one-way ANOVA and Tukey HSD tests (p value<0.05). The flexural strength of self-cured acrylic resin with the addition of 1% SEGF and 1% SEGF/UHMW-PE (50.93, 46.13 MPa) was significantly higher than that of the control group (41.72 MPa) (p < 0.05). Nonetheless, the addition of 1% UHMW-PE (39.34 MPa) showed the lowest flexural strength, significantly lower than other experimental groups, except the control group. The addition of 1% SEGF significantly improves the flexural strength of the self-cured acrylic resin denture base.