Ozone is a harmful tropospheric pollutant, causing the formation of reactive oxygen and nitrogen species that lead to oxidative damage in living beings. NF-κB can be activated in response to oxidative damage, inducing an inflammatory response. Nowadays, there are no reliable results that consolidate the use of antioxidants to protect from damage caused by ozone, particularly in highly polluted cities. Curcumin has a strong antioxidant activity and is a potent inhibitor of NF-κB activation with no side effects. The aim of this study is to evaluate the effect of curcumin in preventive and therapeutic approaches against oxidative damage, NF-κB activation, and the rise in serum levels of IL-1β and TNF-α induced by acute and chronic exposure to ozone in rat hippocampus. One hundred male Wistar rats were distributed into five groups; the intact control, curcumin-fed control, the ozone-exposed group, and the preventive and therapeutic groups. These last two groups were exposed to ozone and received food supplemented with curcumin. Lipid peroxidation was determined by spectrophotometry, and protein oxidation was evaluated by immunodetection of carbonylated proteins and densitometry analysis. Activation of NF-κB was assessed by electrophoretic mobility shift assay (EMSA), and inflammatory cytokines (IL-1β and TNF-α) were determined by ELISA. Curcumin decreased NF-κB activation and serum levels of inflammatory cytokines as well as protein and lipid oxidation, in both therapeutic and preventive approaches. Curcumin has proven to be a phytodrug against the damage caused by the environmental exposure to ozone.