Background: Ulcerative colitis is characterized by relapsing inflammation in the gastrointestinal tract with limited treatment options. The aim of the present study was to assess the anti-inflammatory effect of Suppressor of cytokine signaling ( SOCS1 ) on lipopolysaccharide-stimulated RAW264.7 cells and to investigate its potential mechanisms. Methods: The in vitro ulcerative colitis model was established by using lipopolysaccharide-stimulated RAW264.7 cells. Western blotting was used to detect the protein expression levels of SOCS1 , JAK2 , STAT3 , and VDR . Reverse transcription-quantitative polymerase chain reaction was used to measure the mRNA expression of SOCS1 , miR-222-3p, and VDR . An enzyme-linked immunosorbent assay was performed to measure the levels of inflammatory cytokines. A luciferase assay assessed the binding of SOCS1 to miR-222-3p. A total of 15 patients with ulcerative colitis and 18 healthy controls were recruited. The expression levels of SOCS1 and miR-222-3p in the colonic mucosa tissues of patients with ulcerative colitis and healthy controls were determined by reverse transcription-quantitative polymerase chain reaction. Results: SOCS1 upregulation inhibited the lipopolysaccharide-induced inflammation in RAW264.7 cells. SOCS1 was confirmed to be targeted by miR-222-3p. Silencing SOCS1 significantly abolished the inhibitory effects of miR-222-3p downregulation on inflammation. MiR-222-3p activated STAT3 signaling and reduced VDR expression by targeting SOCS1 in lipopolysaccharide-treated RAW264.7 cells. Additionally, miR-222-3p expression was upregulated in ulcerative colitis patients ( P = 5.16E−10), while SOCS1 ( P = 2.75E−10) and VD R ( P = 52.5E−9) expression was downregulated in ulcerative colitis patients. Endoscopic scores (UCEIS) revealed significant positive correlation with miR-222-3p and negative correlation with SOCS1 and VDR . Conclusion: MiR-222-3p targets SOCS1 to aggravate the inflammatory response by suppressing VDR and activating STAT3 signaling in ulcerative colitis.