A gene therapy treatment with plasmid-based growth hormone-releasing hormone (GHRH) delivered by electroporation (EP) was investigated during heat stress; 32 primiparous cows received 2.5 mg of a GHRH-expressing myogenic plasmid (pSP-HV-GHRH), while 20 were designated as controls. Offspring of treated animals showed a reduction in mortality (47%; p < 0.02), and survival from birth to 260 days was dramatically improved (0% mortality vs. 21% in controls) along with an increase in weight gain (p < 0.05). Milk production was increased compared to controls with an average yield gain of 421 kg/cow (p = 0.028). Prolactin (PRL) levels were also significantly increased compared to controls (p < 0.05). The second pregnancy rate was improved by GHRH treatment (53.3% vs. 30.8%). This study shows that the use of plasmid-mediated therapy delivered by EP can maintain health status during periods of heat stress, important for both animals and potentially humans in hot, challenging climates.