Autophagy dysfunction has been observed in intervertebral disc degeneration (IVDD) cells, a main contributing factor to cell death, but the precise role of autophagy during IVDD is still controversial. This study aimed to investigate the role of autophagy involved in the pathogenesis of human IVDD and determine the signal transduction pathways responsible for compression-induced autophagy in human nucleus pulposus (NP) cells. Autophagy, suppressing the induction of apoptosis, was activated in NP cells exposed to compression. Molecular analysis showed that compression promoted the activity of NRF1, a transcription regulator increasing Atg7 expression by binding to its promoter, through activating the Ras/MEK/ERK signaling in NP cells. Loss- and gain-of-function studies demonstrate that NRF1 induced autophagy and dampened the apoptotic response by promoting Atg7 expression in NP cells subjected to compression. This study confirmed that compression-induced autophagy could be induced by Ras via MEK/ERK/NRF1/Atg7 signaling pathways, while inhibiting Ras/MEK/ERK/NRF1/Atg7 signaling pathways attenuated this autophagic process, implicating a promising therapeutic strategy for IVDD.