Secreted protein acidic and rich in cysteine (SPARC) has a close association with inflammatory response and oxidative stress in tissues and is widely expressed in intracranial aneurysms (IAs), especially in smooth muscle cells. Therefore, it is inferred that SPARC might be involved in the formation and development of IAs through the inflammatory response pathway or oxidative stress pathway. The aim of this study is to investigate the pathological mechanism of SPARC in oxidative stress, inflammation, and apoptosis during the formation of IAs, as well as the involvement of TGF-β1 and NOX4 molecules. Human brain vascular smooth muscle cells (HBVSMCs) were selected as experimental objects. After the cells were stimulated by recombinant human SPARC protein in vitro, the ROS level in the cells was measured using an ID/ROS fluorescence analysis kit combined with fluorescence microscope and flow cytometry. The related protein expression in HBVSMCs was measured using western blotting. The mitochondrial membrane potential change was detected using a mitochondrial membrane potential kit and laser confocal microscope. The mechanism was explored by intervention with reactive oxygen scavengers N-acetylcysteine (NAC), TGF-β1 inhibitor (SD-208), and siRNA knockout. The results showed that SPARC upregulated the expression of NOX4 through the TGF-β1-dependent signaling pathway, leading to oxidative stress and pro-inflammatory matrix behavior and apoptosis in HBVSMCs. These findings demonstrated that SPARC may promote the progression of IAs.