Bitter gourd (Momordica charantia L.), grown in semi-arid and fragile soil, exhibits poor growth, yield loss, and reduced quantity of bioactive compounds which may be improved by seed priming with bio-rationale materials. A field experiment was undertaken from March to June 2022 to determine the efficacy of zinc oxide nanoparticles (ZnONPs) on bitter gourd growth, yield, and some phytochemical contents through seed priming. Plants of bitter gourd were divided into five sets. The first set served as a control and was not treated with ZnONPs. The plants of sets 2, 3, 4, and 5 were treated with ZnONPs primed seed at 0.5, 0.10, 0.15, or 0.20 mL∙L−1 concentrations, and priming duration of 24 h. Seed priming with 0.20 mL∙L−1 improved vine length, number of leaves, and number of branches per plant by 46, 21, and 39% compared to the control. Days to plant emergence and flowering were reduced and yield attributes improved by seed priming. Total phenolic, total flavonoids, and charantin, a steroidal saponin, contents as major secondary metabolite of fresh fruit of bitter gourd improved by 47, 36, and 52% treated with 0.20 mL∙L−1 of ZnONPs primed seed. Seed priming with ZnONPs could be used to improve growth, germination, important metabolites and yield of bitter gourd.