LPS could seriously damage the kidney. FA pretreatment could upregulate AMPKα1 expression and phosphorylation, inhibite the release of inflammatory cytokines, maintain the mitochondrial function, improve energy supply and redox equilibrium, alleviate apoptosis, and ultimately protect renal tissue against LPS damage. Display omitted •Ferulic acid (FA) pretreatment protected the renal tissue against LPS damage.•FA pretreatment alleviated apoptosis by upregulating AMPKα1 expression and phosphorylation.•Protective mechanism of FA was associated with inhibited the release of inflammatory cytokines and oxidative stress. The kidney is susceptible to lipopolysaccharide (LPS)-induced damage with sepsis, and renal dysfunction is a leading cause of mortality in patients with sepsis. However, the renoprotective effects of ferulic acid (FA) during sepsis and the underlying mechanism remain unclear. This study explored these renoprotective effects using NRK-52E cells and mice with LPS-induced renal damage. The results showed that after LPS challenge, NRK-52E cell viability decreased, whereas lactate dehydrogenase, caspase-3 activity, apoptosis, the release of the inflammatory cytokines, and reactive oxygen species generation increased. Further, the activities of endogenous enzymatic and non-enzymatic antioxidant systems, and energy metabolism were inhibited, mitochondrial membrane potential was lost, mitochondrial permeability transition pores opened, renal blood flow and excretory functions were reduced, and the morphology and ultrastructure of renal tissue were seriously damaged in mice exposed to LPS. FA pretreatment upregulated AMP-activated protein kinase (AMPK) α1 expression and phosphorylation and significantly reversed the aforementioned functional, enzymological, and morphological indexes in vivo and in vitro. However, these renoprotective effects of FA were attenuated by compound C, an AMPK inhibitor. In conclusion, FA pretreatment can upregulate AMPKα1 expression and phosphorylation, inhibit inflammatory cytokine release and oxidative stress, improve mitochondrial function and energy supply, alleviate apoptosis, and ultimately protect renal tissue against LPS damage.