The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway is a pivotal innate immune mechanism for sensing cytosolic double-stranded DNA. Its canonical role is to exert antiviral immunity by inducing the expression of type I interferons and pro-inflammatory cytokines. However, recent studies have revealed that key components of this pathway possess non-canonical functions capable of inducing autophagy through diverse mechanisms. Recent studies have revealed that STING can also drive lysosomal biogenesis mediated by transcription factor EB(TFEB). These findings suggest that the cGAS-STING axis serves as a critical bridge linking innate immunity with the autophagy-lysosomal system. The activation of this pathway yields pleiotropic effects, ranging from homeostatic preservation to the aggravation of disease progression, depending on the specific pathological milieu. This review aims to summarize the latest advances in the molecular mechanisms and pathophysiological roles of the cGAS-STING-mediated activation of the autophagy-lysosomal system, providing a comprehensive framework for understanding its biological functions and informing potential therapeutic strategies for related diseases.