This research evaluated the protective role of a combined extract of Dioscorea bulbifera and Zingiber officinale (DBZO) against respiratory dysfunction caused by particulate matter (PM2.5) exposure in BALB/c mice. The bioactive compounds identified in the DBZO are catechin, astragalin, 6-gingerol, 8-gingerol, and 6-shogaol. DBZO ameliorated cell viability and reactive oxygen species (ROS) production in PM2.5-stimulated A549 and RPMI 2650 cells. In addition, it significantly alleviated respiratory dysfunction in BALB/c mice exposed to PM2.5. DBZO improved the antioxidant systems in lung tissues by modulating malondialdehyde (MDA) content, as well as levels of reduced glutathione (GSH) and superoxide dismutase (SOD). Likewise, DBZO restored mitochondrial dysfunction by improving ROS levels, mitochondrial membrane potential, and ATP production. Moreover, DBZO modulated the levels of neutrophils, eosinophils, monocytes, and lymphocytes (specifically CD4+, CD8+, and CD4+IL-4+ T cells) in blood and IgE levels in serum. DBZO was shown to regulate the c-Jun N-terminal kinase (JNK) pathway, nuclear factor kappa B (NF-κB) pathway, and transforming growth factor β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) pathway. Histopathological observation indicated that DBZO mitigates the increase in alveolar septal thickness. These findings indicate that DBZO is a promising natural agent for improving respiratory health.