Oxidative stress and inflammation are the major pathological mechanisms implicated in renal injures including acute kidney injury and chronic kidney disease. Moreover, oxidative stress is also a key detrimental factor that can lead to inflammation. Therefore, targeting oxidative stress and inflammation has been thought to be a promising approach for fighting kidney disease. In this chapter, we discuss the role of a natural product β-lapachone and its anti-oxidative stress and anti-inflammation properties in animal models of kidney injury. These models include kidney injury induced by cisplatin, ischemia, diabetes, high salt intake, and doxorubicin. In particular, we focus on NAD(P)H-quinone oxidoreductase 1 (NQO1) as it is a major cellular target of β-lapachone involving a futile cycle whereby NQO1 reduces β-lapachone to a semiquinone at the expense of NADH or NADPH. We also focus on NADPH oxidase (NOX) as β-lapachone can compete with NOX for NADPH, leading to decreased production of reactive oxygen species (ROS) by NOX and hence mitigated oxidative damage in the kidney. The chapter ends with conclusion and future perspectives on β-lapachone and kidney disease.