A healthy mammary gland is a necessity for milk production of dairy goats. The role of chi-miR-3880 in goat lactation is illustrated in our previous study. Among the differentially expressed genes regulated by chi-miR-3880, one seventh are interferon stimulated genes, including MX1, MX2, IFIT3, IFI44L, and DDX58. As the inflammatory cytokine interferon gamma (IFNγ) has been identified as a potential marker of caseous lymphadenitis in lactating sheep, the interaction between IFNγ and immune-related microRNAs is explored. In this study, it was found that chi-miR-3880 could be one of the microRNAs downregulated by IFNγ in goat mammary epithelial cells (GMECs). The regulation among IFNγ, chi-miR-3880, and DDX58, as well as their roles in mammary gland were investigated. The study illustrated that IFNγ/chi-miR-3880/DDX58 axis modulates GMEC proliferation and lipid formation through PI3K/AKT/mTOR pathway, and regulates apoptosis through Caspase-3 and Bcl-2/Bax. The role of the axis in involution was reflected by the expression of p53 and NF-κB. In conclusion, IFNγ/chi-miR-3880/DDX58 axis plays an important part in lactation.