Lymphatic metastasis is the most common pattern of bladder cancer (BCa) metastasis and has an extremely poor prognosis. Emerging evidence shows that ubiquitination plays crucial roles in various processes of tumors, including tumorigenesis and progression. However, the molecular mechanisms underlying the roles of ubiquitination in the lymphatic metastasis of BCa are largely unknown. In the present study, through bioinformatics analysis and validation in tissue samples, we found that the ubiquitin-conjugating E2 enzymeUBE2Swas positively correlated with the lymphatic metastasis status, high tumor stage, histological grade, and poor prognosis of BCa patients. Functional assays showed thatUBE2Spromoted BCa cell migration and invasion in vitro, as well as lymphatic metastasis in vivo. Mechanistically,UBE2Sinteracted with tripartite motif containing 21 (TRIM21) and jointly induced the ubiquitination of lipoma preferred partner (LPP) via K11-linked polyubiquitination but not K48- or K63-linked polyubiquitination. Moreover,LPPsilencing rescued the anti-metastatic phenotypes and inhibited the epithelial-mesenchymal transition of BCa cells afterUBE2Sknockdown. Finally, targetingUBE2Swith cephalomannine distinctly inhibited the progression of BCa in cell lines and human BCa-derived organoids in vitro, as well as in a lymphatic metastasis model in vivo, without significant toxicity. In conclusion, our study reveals thatUBE2S, by interacting withTRIM21, degradesLPPthrough K11-linked ubiquitination to promote the lymphatic metastasis of BCa, suggesting thatUBE2Srepresents a potent and promising therapeutic target for metastatic BCa.