Drought is considered a major threat to rice production. This study aimed to determine the effects of drought stress on the estimates of heterosis and the combining ability of rice genotypes for the number of days to 50% heading, plant height, number of panicles per plant, panicle length, number of filled grains per panicle, and grain yield per plant. Field experiments were conducted at the Rice Research and Training Center, Kafr El Sheikh, Egypt, during the rice-growing season in 2018 and 2019. Eight rice genotypes (Giza178, Giza179, Sakha106, Sakha107, Sakha108, WAB1573, NERICA4, and IET1444) were crossed in a half-diallel cross in the rice-growing season in 2018, which yielded a wide range of variability in numerous agronomic traits and drought tolerance measurements. In 2019, these parents and their 28 F1 crosses were produced by employing a three-replication randomized complete block design under normal and water stress conditions. The results showed remarkable differences across the studied genotypes under normal and water stress conditions. Under both conditions, Sakha107 was the best general combiner for earliness and short stature. Giza179 and Sakha108 were the best general combiners for grain yield per plant and one or more of its characteristics. Furthermore, in both normal and water stress conditions, Giza179 exhibited the highest general combining ability effects for all attributes that were evaluated. Under normal and water stress conditions, the Giza179 × Sakha107 cross demonstrated substantial and desirable specific combining ability effects on all the examined traits, which suggested that it could be considered for use in rice hybrid breeding programs. Therefore, we recommend that these vital indirect selection criteria to be considered for improving rice grain yield under drought conditions.