Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease with limited therapies. While UFL1-mediated UFMylation has been implicated in various diseases, its role in TNBC remains not fully understood. Here, we demonstrate that AKT1 directly interacts with UFL1 and undergoes UFMylation at Lys189/276/297. This modification enhances AKT phosphorylation and activation, promoting tumor growth and chemoresistance in TNBC. In turn, AKT phosphorylates UFL1 at Thr426, establishing a positive feedback loop that sustains high activity of both pro-oncogenic regulators in TNBC. Disrupting the UFL1-AKT interaction using the specific peptide PDAU-TAT significantly inhibits TNBC progression both in vitro and in vivo. Clinically, elevated pT426 UFL1 correlates with high pAKT in TNBC specimens. These findings uncover a crucial UFL1-AKT positive feedback loop that drives TNBC progression and suggest that targeting this axis could offer a promising therapeutic strategy for TNBC and potentially other aggressive cancers characterized by upregulated UFL1 and AKT activation.