Intervertebral disc degeneration (IDD) is recognized as the major contributor to low back pain, which results in disability worldwide and heavy burdens on society and economy. Here we present evidence that the lower level of Nrf2 is closely associated with higher grade of IDD. The apoptosis and senescence of nucleus pulposus cells (NPCs) were exacerbated by Nrf2 knockdown, but suppressed by Nrf2 overexpression under oxidative stress. Based on findings that Kinsenoside could exert multiple pharmacological effects, we found that Kinsenoside rescued the NPC viability under oxidative stress and protected against apoptosis, senescence and mitochondrial dysfunction in a Nrf2-dependent way. Further experiments revealed that Kinsenoside activated a signaling pathway of AKT-ERK1/2-Nrf2 in NPCs. Moreover, in vivo study showed that Kinsenoside ameliorated IDD in a puncture-induced model. Together, the present work suggests that Nrf2 is involved in the pathogenesis of IDD and shows the protective effects as well as the underlying mechanism of Kinsenoside on Nrf2 activation in NPCs.