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Fenofibrate is a fibric acid derivative used as an antihyperlipidemic drug in humans. Its active metabolite, fenofibric acid, acts as an agonist to the peroxisome proliferator-activated receptor alpha (PPAR-α), a transcription factor involved in different metabolic pathways. Some studies have reported the potential protective role of this drug in cell lines and in vivo models against bacterial and viral infections. The aim of this study was to assess the in vitro effect of fenofibrate in the macrophage cell line J744A.1 against infections produced by <i>Aeromonas</i>, a pathogen for humans whose resistance to antibiotics has increased in recent decades. Macrophages were infected at MOI 10 with four strains of <i>Aeromonas caviae</i> and <i>Aeromonas hydrophila</i> isolated from human clinical samples and subsequently treated with fenofibrate. It was observed that fenofibrate-treated macrophages showed lower levels of cytotoxicity and intracellular bacteria compared to non-treated macrophages. In addition, the viability of treated macrophages was dependent on the dose of fenofibrate used. Furthermore, transcriptional analysis by RT-qPCR revealed significant differences in the expression of the <i>PPAR-α</i> gene and immune-related genes <i>TNF-α</i>, <i>CCL3</i>, and <i>BAX</i> in fenofibrate-treated macrophages compared to the macrophages without treatment. This study provides evidence that fenofibrate offered some protection in vitro in macrophages against <i>Aeromonas</i> infection. However, further studies are needed with other bacteria to determine its potential antibacterial effect and the route by which this protection is achieved.