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CXCR1/2 biomolecules play vital roles in cancer cell proliferation, tumor inflammation, and angiogenesis, making them attractive drug targets. In clear cell renal cell carcinoma (RCC) and head and neck squamous cell carcinoma (HNSCC), where CXCR1/2 is overexpressed, inhibition studies are limited. Building upon previous research efforts, we investigated new N , N '-diarylurea analogues as ELR + CXCL-CXCR1/2 inhibitors. Evaluations on RCC and HNSCC cell lines and 3D spheroid cultures identified compound 10 as a lead molecule, exhibiting significant inhibition of invasion, migration, and neo-angiogenesis. It demonstrated strong interference with the signaling pathway, with high selectivity toward kinases. In vivo studies on zebrafish embryos and RCC xenografted mice showed notable anticancer, antimetastatic, and antiangiogenic effects after oral administration and minimal toxicity. Compound 10 emerges as a promising candidate for further preclinical development as an oral anticancer and antiangiogenic drug targeting the ELR + CXCL-CXCR1/2 pathway., Competing Interests: The authors declare the following competing financial interest(s): L.C.P.G. reports financial support was provided by Roca Therapeutics. O.R. reports financial support was provided by Roca Therapeutics. J.L.D. reports financial support was provided by Roca Therapeutics. M.D. reports a relationship with Roca Therapeutics that includes: board membership. G.P. reports a relationship with Roca Therapeutics that includes: board membership. R.B. reports a relationship with Roca Therapeutics that includes: board membership. C.R. reports a relationship with Roca Therapeutics that includes: board membership. M.D. has Patent WO2020079184A2 licensed to Roca Therapeutics. G.P. has Patent WO2020079184A2 pending to Roca Therapeutics. R.B. has Patent WO2020079184A2 licensed to Roca Therapeutics. C.R. has Patent WO2020079184A2 licensed to Roca Therapeutics. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 American Chemical Society.)