Simple Summary In this study, drug combination screening was used to design a multidrug combination consisting of repurposed drugs to treat sunitinib-resistant clear cell renal cell carcinoma. In the frame of this project, the multidrug combination has been optimized and validated and an insight into the mechanism of action is given. The multidrug combinations significantly altered the transcription of genes related to apoptosis and metabolic pathways. Further analysis of the metabolism revealed strong upregulation of the presence of sphingolipids after multidrug combination treatment. Final evaluation for translation of the multidrug combination in ex vivo organoid-like cultures demonstrated significant anti-cancer efficacy. Repurposed drugs have been evaluated for the management of clear cell renal cell carcinoma (ccRCC), but only a few have influenced the overall survival of patients with advanced disease. To combine repurposed non-oncology with oncological drugs, we applied our validated phenotypic method, which consisted of a reduced experimental part and data modeling. A synergistic optimized multidrug combination (ODC) was identified to significantly reduce the energy levels in cancer remaining inactive in non-cancerous cells. The ODC consisted of Rapta-C, erlotinib, metformin and parthenolide and low doses. Molecular and functional analysis of ODC revealed a loss of adhesiveness and induction of apoptosis. Gene-expression network analysis displayed significant alterations in the cellular metabolism, confirmed by LC-MS based metabolomic analysis, highlighting significant changes in the lipid classes. We used heterotypic in vitro 3D co-cultures and ex vivo organoids to validate the activity of the ODC, maintaining an efficacy of over 70%. Our results show that repurposed drugs can be combined to target cancer cells selectively with prominent activity. The strong impact on cell adherence and metabolism indicates a favorable mechanism of action of the ODC to treat ccRCC.