Inhaling particulate matter with an aerodynamic diameter of ≤ 2.5 µm (PM2.5) has been demonstrated to induce season-dependent adverse health effects. As inflammation and oxidative stress play a critical role in PM2.5-induced health effects, this study used a human monocytic cell line, THP-1, to investigate whether the PM2.5-induced oxidative stress and pro-inflammatory response varied by season. PM2.5 was collected during April (spring), July (summer), September (fall) and December (winter) of 2014. The cytotoxicity was assessed with a lactate dehydrogenase (LDH) release assay. The levels of pro-inflammatory mediators, including tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β), were measured with ELISA, and the reactive oxygen species (ROS) were identified with flow cytometry. Sulforaphane (SFN), an antioxidant, was used to determine whether ROS regulated the PM2.5-induced expression of pro-inflammatory mediators. The PM2.5 from winter exhibited the highest potency in inducing cytotoxicity as well as the production of TNF-α and IL-1β from THP-1 cells; the same was true for ROS production. Further experiments demonstrated that pretreating THP-1 cells with SFN markedly mitigated the winter-PM2.5-induced release of TNF-α and IL-1β. Composition analysis revealed that the PM2.5 contained higher levels of anions (NO3– and SO42–) and water-soluble metals (Al, Ca, Mg, Zn and Cr) during summer and winter than spring and fall. In summary, PM2.5-induced oxidative stress and the subsequent production of pro-inflammatory mediators vary by season.