Acute kidney injury (AKI) is a prevalent clinical condition that is associated with unacceptably high morbidity and mortality, as well as the development of chronic kidney disease (CKD). The pathogenesis of AKI is highly complex and heterogeneous, primarily attributed to metabolic disturbances arising from the disease itself and the administration of medications related to treatment. In recent years, AKI in cancer patients is highly concerned. The emergence of AKI caused injuries and dysfunction of remote organs but also enhanced the health-care costs. It's essential for early recognition of AKI by biomarker or prediction models and further, take a timely intervention. This review aims to provide the pathophysiology of AKI covering the intricate mechanisms underpinning AKI in the dynamic context of the clinical setting, the tailored role of inflammation and ischemia, and the cellular and molecular crosstalk pathways involved. These events closely related to patients at high risk of AKI and underscore the characteristics that may make these patients more susceptible to injury. Furthermore, the diagnosis of AKI relies on clinical criteria, biomarkers, and imaging, but it should be distinguished from CKD. Finally, the review offers the therapeutic intervention in clinical practice and preclinical or clinical trials, focusing on the improvement of conventional therapy and advanced novel treatment strategies. Simultaneously, the challenge and future direction on early identifying renal impairment and performing renoprotection are also discussed, further supporting the novel discipline including onco-nephrology. The development of effective interventions that reduce nephrotoxicity is highly contingent upon a thorough understanding of the molecular pathophysiology of AKI.