Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Fine particulate matter (PM2.5) is associated with increased risk of lung cancer. microRNAs (miRNAs) play an important role in a variety of cancers, including NSCLC. In NSCLC, existing literature has revealed upregulation of miR-21-5p. Nonetheless, the molecular mechanism of miR-21-5p in NSCLC development after PM2.5 exposure is not clear. This study aimed to investigate the role of miR-21-5p in NSCLC development after PM2.5 exposure and to elucidate the underlying molecular mechanisms. Expression of miR-21-5p, <i>PDE4DIP</i>, and <i>SORBS2</i> was determined in NSCLC cell lines and tumor tissues. To measure proliferation, migration/invasion of NSCLC cells, 3-(4, 5-dimethyl-thiazolyl-2)-2, 5-diphenyl-tetrazolium bromide (MTT), colony formation, transwell and wound healing assays were accordingly performed. A tumor xenograft model was established to evaluate the effects of miR-21-5p, <i>PDE4DIP</i>, and <i>SORBS2</i> modification on tumor growth <i>in vivo</i>. miR-21-5p was up-regulated in NSCLC tumor tissues and cell lines. Also, PM2.5 exposure led to a higher level of miR-21-5p. The miR-21-5p mimic and inhibitor respectively promoted and decreased proliferation and migration/invasion of NSCLC cells. Tumor growth was reduced in miR-21-5p KO mice <i>in vivo</i>. Luciferase reporter assay indicated that <i>PDE4DIP</i> was a target of miR-21-5p. Moreover, miR-21-5p regulated cell proliferation and migration/invasion by inhibiting <i>PDE4DIP</i> expression after PM2.5 exposure. <i>PDE4DIP</i> knockdown promoted tumor growth <i>in vivo</i>. P<i>DE4DIP</i> and <i>SORBS2</i> were down-regulated in NSCLC tumor tissues and cell lines. <i>SORBS2</i> inhibited NSCLC cell proliferation and invasion/migration and tumor growth after PM2.5 exposure by regulating miR-21-5p/PDE4DIP signaling pathway. miR-21-5p could target <i>PDE4DIP</i> and promote tumor growth of NSCLC. <i>SORBS2</i> suppressed NSCLC tumorigenesis by regulating miR-21-5p/PDE4DIP signaling pathway.