Loss of extracellular matrix (ECM) and dehydration of the nucleus pulposus (NP) are major pathological characteristics of intervertebral disc degeneration (IVDD), the leading cause of low back pain. Excessive reactive oxygen species (ROS) induced by proinflammatory cytokines substantially contribute to IVDD pathogenesis. This study aimed to examine the potential of fucoidan in protecting the matrix metabolism of NP cells and its therapeutic efficacy in the prevention of IVDD. In an inflammatory environment induced by interleukin (IL)-1β, fucoidan treatments demonstrated a dose-dependent enhancement of ECM production in NP cells, while concurrently reducing the expression of matrix degradation enzymes. The protective effect of fucoidan was mediated through the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and subsequent induction of antioxidant enzymes, whereas silencing Nrf2 abrogated the protection of fucoidan on NP cells against IL-1β-induced oxidative stress. Moreover, a novel fucoidan-functionalized gelatin methacryloyl microsphere (Fu@GelMA-MS) was synthesized. The in vivo application of Fu@GelMA-MS via in situ injection in a rat caudal IVD model effectively conserved the ECM components and maintained the hydration of the NP tissue, thereby preventing IVDD caused by puncture. Collectively, fucoidan-functionalized hydrogel microspheres represent a promising strategy for the regeneration of NP and the treatment of IVDD.