Ischemic stroke (IS) is one of the major global causes of death and disability. Because blood clots block the neural arteries provoking ischemia and hypoxia in the brain tissue, IS results in irreversible neurological damage. Available IS treatments are currently limited. Curcumin has gained attention for many beneficial effects after IS, including neuroprotective and anti-inflammatory; however, its precise mechanism of action should be further explored. With network pharmacology, molecular docking, and molecular dynamics (MD), this study aimed to comprehensively and systematically investigate the potential targets and molecular mechanisms of curcumin on IS. We screened 1096 IS-related genes, 234 potential targets of curcumin, and 97 intersection targets. KEGG and GO enrichment analyses were performed on these intersecting targets. The findings showed that the treatment of IS using curcumin is via influencing 177 potential signaling pathways (AGE-RAGE signaling pathway, p53 signaling pathway, necroptosis, etc.) and numerous biological processes (the regulation of neuronal death, inflammatory response, etc.), and the AGE-RAGE signaling pathway had the largest degree of enrichment, indicating that it may be the core pathway. We also constructed a protein-protein interaction network and a component-target-pathway network using network pharmacology. From these, five key targets were screened: NFKB1, TP53, AKT1, STAT3, and TNF. To predict the binding conformation and intermolecular affinities of the key targets and compounds, molecular docking was used, whose results indicated that curcumin exhibited strong binding activity to the key targets. Moreover, 100 ns MD simulations further confirmed the docking findings and showed that the curcumin-protein complex could be in a stable state. In conclusion, curcumin affects multiple targets and pathways to inhibit various important pathogenic mechanisms of IS, including oxidative stress, neuronal death, and inflammatory responses. This study offers fresh perspectives on the transformation of curcumin to clinical settings and the development of IS therapeutic agents.