Objectives To determine the role of microRNA-15b (miR-15b) in interleukin-1 beta (IL-1 beta)-induced extracellular matrix (ECM) degradation in the nucleus pulposus (NP). Results MiR-15b was up-regulated in degenerative NP tissues and in IL-1 beta-stimulated NP cells, as compared to the levels in normal controls (normal tissue specimens from patients with idiopathic scoliosis). Bioinformatics and luciferase activity analyses showed that mothers against decapentaplegic homolog 3 (SMAD3), a key mediator of the transforming growth factor-beta signaling pathway, was directly targeted by miR-15b. Functional analysis demonstrated that miR-15b overexpression aggravated IL-1 beta-induced ECM degradation in NP cells, while miR-15b inhibition had the opposite effects. Prevention of IL-1 beta-induced NP ECM degeneration by the miR-15b inhibitor was attenuated by small-interfering-RNA-mediated knockdown of SMAD3. In addition, activation of MAP kinase and nuclear factor-kappa B up-regulated miR-15b expression and down-regulated SMAD3 expression in IL-1 beta-stimulated NP cells. Conclusions MiR-15b contributes to ECM degradation in intervertebral disc degeneration (IDD) via targeting of SMAD3, thus providing a novel therapeutic target for IDD treatment.