Aim To study the effect of miR-223 on vascular inflammation and atherosclerosis, and to provide a new therapeutic target for clinical arteriosclerosis. Methods The miR-223 knockout mice and ApoE knockout mice (ApoE KO) were crossbred to prepare miR-223/ApoE double knockout mice (miR-223/ApoE DKO). The plasma lipid levels of 8-month-old mice were measured. Plaque content in the aortic root and the entire length of the blood vessel were analyzed; Immunohistochemical staining was adapted to detect inflammatory cell infiltration in the plaque; Transcriptomics sequencing was used to analyze the expression of inflammation-related genes in the blood vessel; Screening the microRNA target gene database to find and validate possible target genes. Results Atherosclerosis in aortic root of miR-223/ApoE DKO mice were significantly increased (P<0.05). Immunohistochemical staining showed that more inflammatory cells infiltrated in aortic root of DKO mice; Vascular transcriptomics sequencing revealed that expression of inflammatory genes such as vascular adhesion molecule-1(VCAM-1), interleukin-1α(IL-1α) were up-regulated in DKO mice; Through screening of target genes from database, IL-6 was found to be a potential target gene of miR-223 and its expression was significantly up-regulated in DKO mice; 3T3 cells were transfected with miR-223 mimics and the expression of interleukin-6(IL-6 )was significantly down-regulated. Conclusions miR-223 inhibits the expression of target gene IL-6 and reduces the inflammatory response. Knockout miR-223 significantly increases the level of vascular inflammation and promotes the progression of atherosclerosis.