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The emergence of antibiotic resistant microorganisms possesses a great threat to human health and the environment. Considering the exponential increase in the spread of antibiotic resistant microorganisms, it would be prudent to consider the use of alternative antimicrobial agents or therapies. Only a sustainable, sustained, determined, and coordinated international effort will provide the solutions needed for the future. Plant secondary metabolites show bactericidal and bacteriostatic activity similar to that of conventional antibiotics. However, to effectively eliminate infection, secondary metabolites may need to be activated by heat treatment or combined with other therapies. Cold atmospheric plasma therapy is yet another novel approach that has proven antimicrobial effects. In this review, we explore the physiochemical mechanisms that may give rise to the improved antimicrobial activity of secondary metabolites when combined with cold atmospheric plasma therapy.