Breeding drought-tolerant genotypes using genetic and biochemical tools is an important mitigation strategy to improve stress response and yields in bottle gourd [<em>Lagenaria siceraria</em> (Molina) Standl.]. This current study evaluated the variations among bottle gourd genotypes for potential breeding purposes by establishing the relationship between agronomic traits and the protein profile required for the plants’ resilience against drought stress. The study assessed 12 bottle gourd accessions grown under non-stressed (NS) control conditions and different levels of drought stress (DS) induced by withholding irrigation for 7, 14, and 21 days, using a 12 × 2 × 3 factorial experiment in a randomized complete block design with 3 replicates. Agronomic traits such as the total number of male and female flowers per plant, sex ratio, fruit number and fruit yield per plant (FYPP), and total protein analysis were determined in bottle-gourd plants immediately after the period of stress. Results showed significant differences (<em>p</em><em> </em>< 0.001) among the genotypes × environmental effect for most agronomic traits except the number of days to first flower (DTFF). Among the genotypes, BG-70 and BG-78 recorded the highest FYPP under drought stress conditions, with BG-70 showing similar results even under NS conditions. A positive correlation was found among all the agronomic traits and the total protein contents of the genotypes, especially after 14 days of drought stress. Overall, the results implied that the significant improvements in agronomic traits and unique protein expressions observed in BG-70 and BG-78 potentially confer tolerance to drought stress. Moreover, the high and unique proteins found in all genotypes (BG-48, BG-58, BG-52, BG-70, BG-78, and BG-81) warrant further research on their interaction with the stress, especially when coupled with improved agronomic traits, which could assist in identifying drought stress tolerant genotypes.