Abstract This study aimed to evaluate the effect of radiation therapy (RT) on mechanical properties and translucency of monolithic zirconia. Yttria‐ stabilized zirconia (Y‐PSZ) materials (14 × 4.0 × 1.5 mm) were divided in four experimental groups ( n = 30): High‐translucency/control (HT/C), high‐translucency/irradiated (HT/I), low‐translucency/control (LT/C), low‐translucency/irradiated (LT/I). Irradiated specimens were submitted to a single dose irradiation of 70 Gray. Flexural strength ( n = 10) (FS—3‐point bending test), fatigue limits ( n = 15) at 100,000 cycles (FLs—staircase approach), and translucency ( n = 5) (TP—dental spectrometer) were analyzed. X‐ray diffraction (XRD) and scanning electron microscopy (SEM) were used to characterize the materials. FS and TP data were analyzed by one‐way Analysis of Variance (ANOVA) and Tukey HSD. FLs were analyzed using Dixon and Mood method, and Kaplan–Meier survival analysis. RT affected FS of LT zirconia ( p = .032) but not of HT zirconia ( p = .86). FLs and TP of both materials were not affected by RT ( p > .05). Higher cubic content after RT was observed. In conclusion, RT may affect flexural strength and crystalline content of zirconia‐based materials, but this effect was not observed under fatigue. Translucency of Y‐PSZ restorations is also not affected by RT.