Distant metastasis and acquired resistance pose significant challenges to the effectiveness of chemotherapy and targeted molecular therapies. The tumor microenvironment plays a crucial role in determining cancer cells\' sensitivity or resistance to specific drugs. Matrix metalloproteinase 9 (MMP9) is well known for its role in degrading the extracellular matrix and influencing cancer cell motility. This study aimed to identify compounds that target MMP9 and assess their ability to inhibit cancer cell movement. The antimetastatic effects of monoterpene indole alkaloids (MIAs) were evaluated using various assays, including cell viability (MTT assay), migration and invasion assays, qRT-PCR, pathway-specific gene expression analysis, Western blotting, reporter assays, molecular docking simulations, and target prediction. The results showed that MIAs interact with MMP9 and suppress the expression of key signaling proteins such as phospho-EGFR, phospho-Akt, phospho-JNK, and cyclin D1. Additionally, MIAs exhibited favorable pharmacokinetic properties and drug-like characteristics. Among the tested compounds, lyaloside and 5(S)-5-carbomethoxystrictosidine displayed low cytotoxicity while regulating cancer-related pathways involved in cell migration, invasion, epithelial-mesenchymal transition, and immune evasion. These findings suggest that MIAs have promising antimetastatic potential through MMP9-mediated modulation of cancer signaling, making them potential candidates for therapeutic application at safe dosage levels.