Emerging evidence shows that the AMP-activated protein kinase (AMPK), a critical energy-sensing switch, plays an important role in the pathogenesis and development of obesity-related renal injury. In this review, we summarized the mechanisms underlying the protective effects of AMPK activation against obesity-related renal injury in preclinical studies, with the main purposes of increasing the understanding of AMPK and providing new insights into the future clinical therapeutic strategies. The renoprotective effects of AMPK mainly act by modulating lipid metabolism and autophagy and suppressing oxidative stress, inflammation, and fibrosis. More importantly, we discussed the recent advances in this field that require further investigation. Firstly, the inhibitory effect of AMPK on ferroptosis is a potential mechanism for its protection against renal injury. Secondly, the effect of AMPK on lipolysis is complex: AMPK induces basal lipolysis but also inhibits stimulated lipolysis. Thirdly, statins may play a renoprotective role by activating AMPK. Fourthly, some microRNAs targeting AMPK mRNA have been implicated in diabetic nephropathy in type 2 diabetes. Further, AMPK can regulate the expression of some microRNAs, suggesting that the stable renoprotective effects of AMPK may benefit from its epigenetic regulation. Lastly, several natural compounds and synthetic drugs have been recognized to protect against obesity-related renal injury by activating AMPK and its downstream pathways in animal models. It remains to be seen if combination of newly identified drugs with traditional renoprotective medicine will have any synergistic therapeutic benefits without adding to side effects.