Biological control of microorganisms using enzymes has the potential to become a key component of IPM and resistance management strategies. A serine protease was found to significantly reduce disease severity caused by oomycete and bacterial pathogens. Using commercial enzymes from Novozymes’ diversity collection, in-planta greenhouse assays were conducted to determine the efficacy of serine proteases against Phytothphora infestans, Pseudoperonospora cubensis, Plasmopara viticola and Pseudomonas syringae. Under greenhouse conditions, the enzyme effectively reduced disease severity (>85%) of late blight of tomato and downy mildew of grapes and cucumber. In addition, the enzyme effectively reduced disease severity (>75%) of bacterial speck. Using microscopy and laboratory assays, we elucidated the mode of action in which the protease reduced disease. For P. infestans and P. viticola, zoospores were either lysed or germination was inhibited on the foliar surface and, for P. syringae, biofilm formation was disrupted. This enzyme persists on the foliar surface for 16 days and is UV stable for up to 7 days. When applied at suggested application rates, there were no phytotoxicity effects. The protease is active under a wide range of temperatures and pH levels, with the optimum temperature for activity between 40-60°C. This suggests that the effective concentration may vary in different climates. This serine protease has the potential to offer growers an additional tool for disease and resistance management of oomycetes and bacterial pathogens.