Colorectal cancer is one of the leading causes of highly fatal cancer‐related deaths in the whole world. Fast growth is critical characteristic of colorectal cancer, the underlying regulatory mechanism of colorectal cell fast proliferation remains largely unknown. Here, we reported that activation of metabotropic γ‐Aminobutyric acid receptor (GABABR) signaling significantly inhibited the colorectal cell HT29 proliferation by arresting the cell at G1 phase. Inhibition of GABABR activated GSK‐3β by reducing the phosphorylation level of GSK‐3β. Activation of GSK‐3β blocked the function of GABABR signaling on repressing cell proliferation. We further found that GABABR activation inhibited NF‐κB activity. The promotion of cell proliferation caused by downregulation of GABRBR could be blocked by inhibition of NF‐κB activation. Overall, activation of GABABR leaded to inhibition of GSK‐3β activation to repress the NF‐κB function during colorectal cancer cell proliferation. This study revealed critical function of GABABR/GSK‐3β/NF‐κB signaling pathway on regulating proliferation of colorectal cancer cell, which might provide a potential therapeutic target for clinical colorectal cancer treatment.