Alveolar macrophages are believed to induce oxidative stress via reactive oxygen species (ROS) when silica particles are inhaled. This process can contribute to the pathogenesis of silicosis, but the mechanism is unclear. A traditional Chinese herbal derivative, sodium tanshinone IIA sulfonate (STS), displays significant antioxidant effects. Here, we determine whether STS can attenuate the oxidative stress induced by silica. Traditionally, studies on the toxic effects of silica have focused on monocultures of macrophages or fibroblasts. A coculture model of macrophages (Raw 264.7) and pulmonary fibroblasts (MRC-5) was used in this study to mimic a more in vivo-like environment. We investigated the protective effects of STS on the abnormal proliferation of MRC-5 fibroblasts in an in vitro model. The results showed that fibroblast viability increased with the accumulation of intracellular ROS induced by cocultured Raw 264.7 cells after silica exposure. Treatment with STS markedly ameliorated the silica-induced cell proliferation and oxidative stress. Western blotting and immunofluorescence analysis of the Nrf2 and thioredoxin (Trx) system were conducted, and the results confirmed that treatment with STS enhanced nuclear Nrf2 accumulation and mediated antioxidant Trx system expression. These findings suggest that silica exposure might induce some level of oxidative stress in fibroblasts and that STS might augment antioxidant activities via up-regulation of the Nrf2 and Trx system pathways in MRC-5 cells in vitro.