Inflammation involving the innate and adaptive immune systems is a normal response to infection; however, when allowed to continue unchecked, inflammation may result in several pathologies. Natural molecules with antioxidant properties can target the key players of inflammation and exert beneficial health effects. In this study, human normal bronchial (Beas-2B) and prostate (HPrEpiC) epithelial cell lines were exposed to infectious stimulation and treated with phycocyanin (PC) and palmitoylethanolamide (PEA), with the aim of demonstrating the enhanced antioxidant and anti-inflammatory properties of the combination. The cotreatment protected from cytotoxicity and greatly abated both the production of radical oxygen species (ROS) and the transcription of several inflammatory cytokines. Oxidative stress and inflammation were curtailed by affecting three main pathways: (1) inhibition of cyclooxygenase-2 enzyme and consequent decrease of signaling generating ROS; (2) increased synthesis of glutathione and therefore strengthening of the natural antioxidant defenses of the cells; (3) decreased infection-driven mitochondrial respiratory burst which generates oxidative stress. Based on the mounting interest in using nutraceuticals as adjuvants in the clinical practice, the present study unveils new mechanisms of action and enhanced efficacy of PC and PEA, supporting the possible exploitation of this combination in human disorders.