The potential yield of the sesame (Sesamum indicum L.) crop is difficult to realize as the crop is prone to water-limited conditions due to the consequences of current climate change and water scarcity. Severe moisture deficit drastically affects the crop growth and yield. There is an absolute need to understand different physiological traits and derived indices that can be employed to select moisture stress-tolerant genotypes in sesame. Therefore, an experiments were conducted under irrigated (IR) and deficit soil moisture (DS) stress conditions with a set of twenty-five genotypes. The physiological traits like gas-exchange parameters, relative water content (RWC), leaf area ratio (LAR) and intrinsic water use efficiency (iWUE) increased conferring the moisture stress tolerance along with different indices such as stress tolerance index (STI), mean productivity index (MPI), geometric mean productivity (GMP), yield index (YI), stress tolerance (TOL), and yield stability index (YSI). These indices were derived based on the yield under irrigated (Yp) and stress (Ys) conditions. Seed yield decreased by almost 54%, under DS compared to IR conditions; however, genotypes SI 1802 and SI 9823 had maximum seed yield of 17.98 g and 15.90 g under IR and 11.47 g and 11 g under DS conditions. In addition, the factor analysis revealed that the genotypes SI 1802 and SI 9823 expressed higher values for indices i.e., STI, MPI, and GMP under moisture stress along with higher seed yield. These identified genotypes may be used in breeding programs for the development of varieties.