Background The quality of life for millions of people worldwide is affected by chronic pain. In addition to the effect of chronic pain on well-being, chronic pain has also been associated with poor health conditions and increased mortality. Due to its multifactorial origin, the classification of pain types remains challenging. MicroRNAs (miRNA) are small molecules that regulate gene expression. They are released into the bloodstream in a stable manner under normal and pathological conditions and have been described as potential biomarkers. In the present study, we aimed to investigate whether pain may induce an aberrant, specific dysregulation of miRNA expression, depending on the origin of the pain. Methods and findings To do so, we measured the expression changes of 184 circulating miRNAs (c-miRNAs) in the plasma samples of patients with different origins of chronic musculoskeletal pain. After statistical analyses, we identified seven c-miRNA candidates that were differentially expressed depending on the nociceptive or neuropathic origin of the pain. We then developed a two c-miRNA signature (hsa-miR-320a and hsa-miR-98-5p) that was able to correctly classify the pain type of 70% of the patients from the validation set. Conclusions In conclusion, circulating miRNAs are promising biomarkers to identify and characterize the chronic pain type and to further improve its clinical management.