To evaluate the effect of simultaneous liquid or gel sodium hypochlorite (NaOCl) irrigation on cyclic fatigue of F6 SkyTaper (F6ST) and OneCurve (OC) single files, 180 new 25/0.06 F6ST and OC files were divided into 6 groups (n = 15) for each brand. Groups 1 and 4 included new instruments not exposed to NaOCl at 20 °C and 37 °C, respectively. Groups 2 and 5 included files activated with liquid NaOCl at 20 °C and 37 °C, respectively. Groups 3 and 6 consisted of instruments tested with NaOCl gel at 20 °C and 37 °C, respectively. Instruments were subjected to a fatigue test using a novel customized device. Data were expressed as time to fracture (TtF) and statistically analyzed (p < 0.05) after checking their normality through the Shapiro–Wilk test. Because they were normally distributed, 2-way analyses of variance (ANOVA) and the Tukey multiple comparison post-hoc test were used. Time to fracture of all tested instruments decreased at 37 °C (p < 0.05). At 20 °C, NaOCl improved TtF of F6ST and OC (p < 0.05). NaOCl liquid increased TtF of F6ST (p < 0.05) in comparison with gel, while there was no difference between the two formulations for OC. At 37 °C, both NaOCl formulations had no significant influence on TtF for F6ST, while they increased TtF of OC (p < 0.05). NaOCl improved the cyclic fatigue resistance of OC, independently of the temperature, while for F6ST the negative impact of higher temperature reduced the irrigant benefits.