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Abstract Chronic low back pain (LBP) caused by intervertebral disc (IVD) degradation is a serious socioeconomic burden that can cause severe disabilities. Addressing the underlying pathogenic mechanisms of IVD degeneration may inspire novel therapeutic strategy for LBP. Herein, hypoxic preconditioning improves both the biological function of MSCs in hostile microenvironments and enhances the production of small extracellular vesicles (sEVs) with desirable therapeutic functions. In vitro results reveal that hypoxic preconditional engineering sEVs (HP‐sEVs) alleviate the inflammatory microenvironments of IVD degradation, enhance the proliferation of nucleus pulposus (NP) cells, and promote proteoglycan synthesis and collagen formation. Transcriptomic sequencing reveales the excellent therapeutic effects of HP‐sEVs in promoting extracellular matrix regeneration through the delivery of microRNA(miR)‐7‐5p, which further suppresses p65 production and thus the inhibition of Cxcl2 production. Moreover, in vivo results further confirm the robust therapeutic role of HP‐sEVs in promoting IVD regeneration through the same mechanism mediated by miR‐7‐5p delivery. In conclusion, this study provides a novel therapeutic strategy for treating IVD degradation and is thus valuable for understanding the mechanism‐of‐action of HP‐sEVs in IVD regeneration associated with chronic lower back pain.