Crohn's disease is a recurrent, progressive, immune-mediated inflammatory disease and merely manifests non-specific symptoms at early stage. In this study, we isolated peripheral blood mononuclear cells (PBMCs) to determine whether PBMC miRNAs are reliable biomarkers for Crohn's disease diagnosing and monitoring. 5 Crohn's disease patients and 5 healthy controls were recruited to find differentially expressed miRNAs by next generation sequencing. Candidate PBMC miRNAs were further validated by qRT-PCR in another cohort consisting of 86 Crohn's disease patients and 39 healthy controls. We found PBMC miR-582-5p could diagnose Crohn's disease with the area under receiver operating characteristic curve (AUROC) of 0.701(95%CI 0.606-0.796, p < .001). While PBMC miR-96-5p was significantly higher in active Crohn's disease and correlated with both clinical (ρ = 0.376, p < .001) and endoscopic activity (ρ = 0.512, p = .015). Furthermore, PBMC miR-96-5p had a better performance in recognizing active Crohn's disease with AUROC of 0.727 (95%CI 0.609-0.844, p = .001) than C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and fecal calprotectin. In conclusion, PBMC miR-582-5p may be further utilized as a diagnostic biomarker, while miR-96-5p may be a novel and valuable biomarker in monitoring disease activity.