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Multidrug resistance (MDR) reduces chemotherapy efficacy and contributes to cancer relapse, making the development of low-toxicity MDR reversal agents essential. Xinjiang Euphorbia species have demonstrated potential as natural MDR reversers. This study aimed to identify MDR-reversal components from Xinjiang Euphorbia (Ep-XjC), investigate Rhamnetin's effect on the ABCB1 protein to clarify its MDR-reversal mechanism, provide new insights into Rhamnetin's anti-MDR properties, and support the development and application of anti-MDR constituents from Ep-XjC. Network pharmacology was used to screen compounds and predict targets, molecular docking and dynamics simulations to validate interactions, and in vitro assays to evaluate MDR reversal and ABCB1 modulation. Network pharmacology identified 388 potential target genes and 1732 MDR-related genes, with Rhamnetin (D37) showing the most promising results. Molecular docking and molecular dynamics simulations revealed stable interactions between D37 and ABCB1, the key protein responsible for MDR. Functional validation confirmed that D37 modulated ABCB1's functionality to reverse MDR without affecting its expression. The findings reveal Rhamnetin (D37) as a promising MDR reversal agent by modulating ABCB1 activity, highlighting Ep-XjCEuphorbia bioactive compounds as potential therapeutic strategies against cancer MDR. Further in vivo and clinical validation is warranted.