Objective The effect of polymerization time and resin shade on the depth of cure (DOC) of two nano-hybrid resin composites (Filtek Z250 XT and IPS Empress Direct) was evaluated and compared. Materials and Methods Sixty specimens were prepared from two shades (A1 and A3) of the resin composites. The specimens were allocated into two groups that were further divided into three subgroups depending on the polymerization time (20, 40, and 60 sec; n = 5). After that, the DOC was evaluated by calculating the polymerized part of the specimen’s thickness to the nearest (0.01 mm) using a high-accuracy micrometer. Each specimen was measured three times, and the corresponding mean reading (in mm) was divided by two to obtain the DOC. The data were analyzed using SPSS software, version 20. Descriptive statistics followed by three-way analysis of variance was applied. Multiple comparisons were made using Scheffe post hoc tests (α = 0.05). Results Filtek Z250 XT-A1-60sec presented with the greatest DOC (7.42 ± 0.47 mm), and the lowest DOC was obtained with IPS Empress-A3-20sec (2.31 ± 0.21 mm). The mean DOC of Filtek Z250 XT and IPS Empress Direct resin composites were 6.18 mm and 3.59 mm, respectively. Statistically significant (p < 0.05) difference was observed between the resin composites. The interaction between independent factors, namely composites, resin shade, and polymerization time, revealed that interaction between them contributed significantly to the DOC (p ≤0.05). However, the interaction between resin shade and the polymerization time was insignificant (p = 0.148). Conclusion Filtek Z250 XT demonstrated greater DOC than IPS Empress Direct resin composite. An increase in polymerization time significantly enhanced the DOC of the resin composites irrespective of the resin shade. Regardless of the resin composite tested, DOC was lower for darker shades (A3).