Intervertebral disc degeneration (IDD) has been reported to be a major cause of low back pain. Stachydrine (STA) is present in the fruits juice of the Citrus genus and Leonurus heterophyllus, at non-negligible concentrations. In our study, we examined the protective effects of STA in the inhibition of IDD development as well as its underlying mechanism both in vitro and vivo experiments. In vitro, STA made the protective effects on the anabolism and catabolism of extracellular matrix (ECM) in IL-1β-treated NPCs, and STA inhibited the expression of pro-inflammatory factors. Mechanistically, the STA suppressed IL-1β-induced activation of the PI3K/Akt/NF-κB signalling pathway cascades. Moreover, it was also demonstrated in molecular docking studies that STA had strong binding abilities to PI3K. In vivo, STA ameliorated the IDD process in the puncture-induced rat model. In summary, our findings demonstrated that STA ameliorates the progression of IDD via the PI3K/Akt/NF-κB signaling pathway, which supports STA as a promising therapeutic agent for the treatment of IDD.