Necroptosis, a form of inflammation-related programmed cell death, is a major mechanism of proximal tubular cell injury in acute kidney injury (AKI). Blockade of necroptosis signalling represents a promising strategy for clinical therapy of AKI. Previously, we identified a small molecular receptor-interacting protein kinases (RIPK)1 inhibitor Cpd-71 with nephroprotective activities. To discover more nephroprotective agents, in this study, 20 chalcone derivatives were synthesized and evaluated for their anti-necroptosis and nephroprotective activities. Among the chalcone derivatives, Cpd-2 exhibited the most potent anti-necroptosis activity (IC  = 1.08 μM) and protective activity (EC = 1.49 μM) through directly binding to RIPK1 and blocking RIPK1-RIPK3-mixed-lineage kinase domain-like protein (MLKL) signalling pathway. Furthermore, Cpd-2 effectively attenuated cisplatin or hypoxia/reoxygenation (H/R)-induced injury and necroptotic inflammation in renal cell models. Moreover, in cisplatin- or ischemia/reperfusion (I/R) induced AKI mouse model, detection of creatinine and urea nitrogen in blood showed that Cpd-2 improved kidney function. Periodic acid-Schiff (PAS) staining and immunofluorescence analysis indicated that Cpd-2 also reduced pathological damage and inhibited inflammatory development in kidney tissues. In summary, although some chalcone derivatives have been reported to prevent kidney injury previously, our present study not only discovered a promising leading compound Cpd-2, but also provided a novel and successful practice for the development of necroptosis inhibitors from natural products derivatives as AKI therapeutic agents.