Objective To establish an inflammation model in neonatal SD rats and to explore the mechanism by which microRNA-219 (miR-219) promotes oligodendrocyte maturation. Methods Sixty SD rats were randomly assigned to control group, lipopolysaccharide ［LPS］ group (LPS 0.15 mg/kg, intraperitoneal injection), LPS＋miR-219 agomir group (LPS 0.15 mg/kg, intraperitoneal injection; miR-219 agomir 3 μL, intraventricular injection), miR-219 antagomir group (miR-219 antagomir 3 μL, intraventricular injection), or LPS＋miR-219 agomir＋U0126 group (LPS 0.15 mg/kg, intraperitoneal injection; miR-219 agomir 3 μL, intraventricular injection; U0126 30 mg/kg, intraperitoneal injection). The rats were sacrified on the 7^th and 14^th day of life and the brain tissue was harvested. The expression levels of miR-219 and inflammatory factors interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) mRNA were detected by quantitative polymerase chain reaction. The expression levels of myelin basic protein (MBP) and extracellular signal-regulated kinase 1/2 (ERK 1/2) were detected by Western blotting. The number of oligodendrocytes in the corpus callosum was observed by immunofluorescence. Results Compared with the control group, the expression levels of IL-1β and TNF-α mRNA were significantly increased after intraperitoneal injection of LPS in rats (both P＜0.01), and the expression of miR-219 was significantly decreased (P＜0.01). Compared with the LPS group, the expression levels of MBP and ERK 1/2 were significantly increased after miR-219 agomir was used to enhance the expression of miR-219 in the brain of rats (both P＜0.01), with increased oligodendrocytes in the corpus callosum. Compared with the control group, the expression levels of MBP and ERK 1/2 were significantly decreased after miR-219 antagomir was used to reduce the expression of miR-219 in the brain of rats (both P＜0.01), with decreased oligodendrocytes in the corpus callosum. After treatment with the ERK 1/2 pathway inhibitor U0126, the maturation promoting effect of miR-219 on oligodendrocytes was significantly inhibited (P＜0.01). Conclusion miR-219 can promote the maturation of oligodendrocytes in rat brain through the ERK 1/2 pathway.