Few studies have focused on the association between previous particulate matter (PM) exposure and antioxidant defense response to a haze challenge. In this study, a combined exposure model was used to investigate whether and how PM exposure history affected the antioxidant defense response to haze episodes. At first, C57BL/6 male mice were randomly assigned to three groups and exposed for 5 weeks to whole ambient air, ambient air containing a low (≤75 μg/m3) PM concentration, and filtered air, which simulated different exposure history of high, relatively low, and almost zero PM concentrations. Thereafter, all mice underwent a 3-day haze exposure followed by a 7-day exposure to filtered air. The indexes involved in the primary and secondary antioxidant defense response were determined after pre-exposure and haze exposure, as well as 1 day, 3 days, and 7 days after haze exposure. Our research demonstrated repeated exposure to a high PM concentration compromised the antioxidant defense response and was accompanied by an increased susceptibility to a haze challenge. Conversely, mice with a lower PM exposure developed an oxidative stress adaption that protected them against haze challenge more efficiently and in a more timely manner than was the case in mice without PM exposure history.