Fine particulate matter (PM_2.5) and sulfur dioxide (SO₂) are 2 common air pollutants, but their toxicological effects of coexposure are still not fully clear. In this study, SO₂ exposure (5.6 mg/m³) couldn’t cause obvious inflammatory responses in rat lungs. The PM_2.5 exposure (1.5 mg/kg body weight) increased inflammatory cell counts in bronchoalveolar lavage fluid (BALF) and some inflammation damage. Importantly, SO₂ and PM_2.5 (1.5, 6.0, and 24.0 mg/kg) coexposure induced pathological and ultrastructural damage and raised inflammatory cells in BALF compared with the control. Also, they significantly elevated the levels of pro-inflammatory cytokines, adhesion molecule, and nitric oxide (NO) and promoted the gene expression of nuclear factor kappa B (NF-κB), phosphorylated p38 (p-p38), and Toll-like receptor 4 (TLR4) in rat lungs treated with higher dose of PM_2.5 (6.0 and 24.0 mg/kg) plus SO₂ relative to the control or SO₂ group, along with the decreased inhibitor of NF-κBα and increased inhibitor of NF-κB kinase β expressions. The changes in the inflammatory markers in the presence of PM_2.5 plus SO₂ were not significant compared with the PM_2.5 group. The results indicated that inflammatory injury and pathological and ultrastructural damage in rat lungs exposed to PM_2.5 plus SO₂ were involved in TLR4/p38/NF-κB pathway activation accompanied by oversecretion of pro-inflammatory cytokine, adhesion molecule, and NO. It provides more useful evidence to understand the possible toxicological mechanism that PM_2.5 and SO₂ copollution exacerbate lung disease.