The impact of particulate matter (PM) on health is an ongoing concern, with PM2.5 pollution being implicated in a broad spectrum of negative health outcomes, including cardiovascular and respiratory diseases, metabolic disorders, and various mood disorders. Despite significant research efforts, the exact mechanisms through which these particles exert their harmful effects remain largely elusive. In our current study, we utilized a sophisticated small animal whole-body inhalation exposure system to closely examine diesel engine exhaust particles (DEPs), aiming to replicate real-world atmospheric conditions as accurately as possible. The focus of our investigation was to scrutinize potential depression-like symptoms in mice subjected to long-term exposure to these particles, with insights into the molecular underpinnings offered via cutting-edge RNA sequencing techniques. In this study, we utilized male BALB/C mice that were systematically exposed to DEPs over varied durations. Behavioral assessments and pathological analyses of mice exposed to DEPs for 6, 8, and 10 weeks were conducted and juxtaposed with those from unexposed control groups. The findings revealed a discernable onset of depression-like behaviors in mice after 6, 8 and 10 weeks of DEP exposure, identifiable through behavioral testing and microscopic tissue examinations. Furthermore, RNA sequencing results suggested that the depression-like behaviors observed in DEP-exposed mice might be intricately tied to the modulation of both pro-inflammatory and anti-inflammatory cytokines, along with alterations in the BDNF pathways in brain regions such as the hippocampus and olfactory bulb. This evidence underscores the notion that exposure to DEPs could potentially instigate depressive patterns in a controlled murine model.