Indian squash (Praecitrullus fistulosus) crop faces heat and drought during its growth that is considered the most important abiotic stress in semi-arid areas. Seed priming with growth regulators enhances stress tolerance; hence, mitigates the adverse effects of unpredictable stresses due to adverse weather conditions. This two-year (2019 and 2020) study was conducted to infer the role of seed priming in improving heat tolerance of Indian squash (cultivar Sahavi) through improvement in physiological and antioxidant defense systems. Six treatments that included no priming (control), hydropriming, priming with indole acetic acid (IAA) at 100 mg L-1, salicylic acid (SA) at 50 mg L-1, ascorbic acid (AA) at 100 mg L-1 and thiourea at 500 mg L-1 each for 06 hours) were included in the study. Results revealed that priming with AA and SA significantly (P ≤ 0.05) enhanced germination (39 and 47%), germination index (57 and 58%), plant height (23 and 22%), vine length (15 and 14%), number of fruits per plant (62%), fruit weight per plant (66 and 67%), economic yield (32%), photosynthesis rate (18 and 17%), protein content (10%), proline (23%), glycine betaine (3%), malondialdehyde content (11 and 10%) and catalase activity (24%) compared to control treatment. Furthermore, seed priming with AA and SA significantly (P ≤ 0.05) shortened the mean germination time (25 and 28%) compared to the control. The results indicated that AA and SA had significant potential to mitigate adverse effects of heat stress in Indian squash. Findings from this study showed that seed priming with AA and SA promoted heat-stress tolerance and enhanced growth and productivity of Indian squash.