We employed an in vivo assay system of Caenorhabditis elegans to determine if and which microRNAs (miRNAs) were dysregulated upon exposure to coal combustion related fine particulate matter (PM2.5) by profiling the miRNAs using SOLiD sequencing. From this, expression of 25 miRNAs was discovered to become dysregulated by exposure to PM2.5. Using the corresponding C. elegans deletion mutants, 5 miRNAs (mir-231, mir-232, mir-230, mir-251 and mir-35) were found to be involved in the control of PM2.5 toxicity. Furthermore, mutation of mir-231 or mir-232 induced a resistance to PM2.5 toxicity, whereas mutation of mir-230, mir-251, or mir-35 induced a susceptibility to PM2.5 toxicity. SMK-1, an ortholog of the mammalian SMEK protein, was identified as a molecular target for mir-231 in the regulation of PM2.5 toxicity. In addition, the genes of sod-3, sod-4 and ctl-3, which are necessary for protection against oxidative stress, were determined to be important downstream targets of smk-1 in the regulation of PM2.5 toxicity. The triggering of this mir-231-SMK-1-SOD-3/SOD-4/CTL-3 signaling pathway may be a critical molecular basis for the role of oxidative stress in the induction of coal combustion related PM2.5 toxicity.