Nutritional deprivation is a critical pathological factor in intervertebral disc degeneration (IVDD), given the disc's avascular nature and its dependence on diffusion through the endplate for nutrient supply. This study investigated the effects of serum deprivation on autophagic flux and apoptosis in human nucleus pulposus (NP) cells, with implications for regenerative strategies in IVDD. Huma NP cells were isolated from surgically obtained human disc tissues from surgeries of disc herniations. To simulate progressive nutrient deprivation, NP cells were cultured under varying fetal bovine serum (FBS) concentrations (10%, 1%, and 0%). Morphological changes, cell viability, DNA content, and metabolic activity were evaluated. Western blotting quantified LC3, P62, HMGB1, and cleaved caspase-3. Apoptotic cell populations were measured by fluorescence-activated cell sorting (FACS). Immunofluorescence staining for LC3, P62, and cleaved caspase-3 assessed autophagic and apoptotic localization. RT-qPCR was performed to analyze expression levels of autophagy-related genes (LC3, P62) and apoptosis-related genes (Caspase-3). As a result, serum deprivation induced marked reductions in NP cell viability, altered morphology, and decreased metabolic activity in a dose- and time-dependent manner, with maximal effects at 48 hours in 0% FBS. Lower serum concentrations triggered increased autophagic activity, evidenced by LC3-II accumulation and P62 degradation, and enhanced expression of LC3 mRNA. Chloroquine treatment confirmed increased autophagic flux by preventing lysosomal degradation of LC3-II. HMGB1 translocated from the nucleus to the cytoplasm under nutrient stress, further supporting autophagy activation. Concurrently, caspase-dependent apoptosis was observed, with elevated cleaved caspase-3 protein and increased Caspase-3 mRNA levels. FACS analysis revealed significant increases in apoptotic cell populations under 0% FBS conditions. Immunofluorescence confirmed co-localization of LC3 and cleaved caspase-3, indicating simultaneous autophagy and apoptosis under nutrient deprivation. In conclusion, serum deprivation robustly induces autophagic flux and caspase-dependent apoptosis in human NP cells, highlighting the critical role of nutritional supply in disc cell survival. The interplay between autophagy and apoptosis under nutrient stress may represent a key mechanism in IVDD progression. Clinically, these findings underscore the potential of therapeutic strategies aimed at restoring nutrient microenvironments or modulating autophagy–apoptosis balance to preserve NP cell viability and promote intervertebral disc regeneration.