ZrO2 nanoparticles (ZNPs) have excellent physical properties. This study investigated the fracture load of implant-supported, fixed cantilevered prosthesis materials, reinforced with ZNPs and various polymerization techniques, compared with conventional and CAD/CAM materials. Sixty specimens were made from two CAD/CAM; milled (MIL) (Ceramill TEMP); and 3D-printed (NextDent Denture 3D+). Conventional heat-polymerized acrylic resin was used to fabricate the other specimens, which were grouped according to their polymerization technique: conventionally (HP) and autoclave-polymerized (AP); conventionally cured and reinforced with 5 wt% ZNPs (HPZNP); and autoclave reinforced with 5 wt% ZNPs (APZNP). The specimens were thermocycled (5000 cycles/30 s dwell time). Each specimen was subjected to static vertical loading (1 mm/min) using a universal Instron testing machine until fracture. Scanning electron microscopy was used for fracture surface analyses. The ANOVA showed significant fracture load differences between all the tested groups (p = 0.001). The Tukey post hoc tests indicated a significant difference in fracture load between all tested groups (p ˂ 0.001) except HP vs. HPZNP and AP vs. MIL. APZNP had the lowest mean fracture load value (380.7 ± 52.8 N), while MIL had the highest (926.6 ± 82.8 N). The CAD/CAM materials exhibited the highest fracture load values, indicating that they could be used in long-term interim prostheses. Autoclave polymerization improved fracture load performance, whereas ZrO2 nanoparticles decreased the fracture load performance of cantilevered prostheses.