Microglia polarization is associated with the pathogenesis of depression. A previous study shows that long non‐coding RNA uc.80‐ is down‐regulated in the hippocampus of depressed rats. Thus, this article aims to investigate the role of uc.80‐ in microglia polarization in depression. We first established depression model rats by chronic unpredictable mild stress (CUMS) regiment. We found that hippocampus of depressed rats exhibited an increase of M1 microglias and a decrease of M2 microglias. uc.80‐ was down‐regulated in hippocampus of depressed rats. Furthermore, the detection of behaviouristics of depressed rats showed that uc.80‐ overexpression alleviated depression of rats. In addition, uc.80‐ overexpression promoted M2 polarization of microglias in vivo and in vitro. uc.80‐ overexpression led to a decrease in apoptosis of hippocampal neurons in vivo and in vitro. In conclusion, our study confirms that lncRNA uc.80‐ overexpression ameliorates depression in rats by promoting M2 polarization of microglias. Thus, our work suggests that uc.80‐ may be a target gene for depression treatment.