Oil and gas extraction in the western United States generates significant volumes of produced water (PW) that is typically injected into deep disposal wells. Recently, crop irrigation has emerged as an attractive PW reuse option, but the impact on plant immune response is not known. In this study, we conducted a 3-month greenhouse pot study. Spring wheat (Triticum aestivum) was irrigated 3 times a week with 150 mL (∼80−100% of soil water holding capacity) with one of four irrigation treatments: tap water control, 10% PW dilution, 50% PW dilution, and salt water (NaCl50) control containing the same amount of total dissolved solids as PW50 to determine the effect on disease resistance. The wheat leaves were inoculated with either bacterial or fungal pathogens and changes in pathogenesis-related PR-1 and PR-5 gene expression were measured from the leaf tissue. PW50 experienced the largest relative suppression of PR-1 and PR-5 gene expression compared to noninfected wheat, followed by PW10, NaCl50, and the tap water control. A combination of PW contaminants (boron, total petroleum hydrocarbons, and NaCl) are likely reducing PR-gene expression by reallocating metabolic resources to fight abiotic stresses, which then makes it more challenging for the plants to produce PR genes to fight pathogens. This study provides the first evidence that plant disease resistance is reduced due to irrigation with reused PW, which could have negative implications for food security.