Metastasis remains the leading cause of death among patients with non-small cell lung cancer (NSCLC), emphasizing the urgent need for safer and more effective therapeutic options. Mitogen-activated protein kinase (MAPK) pathways play a crucial role in regulating EMT, migration, and invasion in NSCLC. Targeting these molecular mechanisms has become a key strategy in inhibiting NSCLC metastasis. Loureirin A and Loureirin B, flavonoids derived from the Thai traditional herb Dracaena loureiri, have shown potential pharmacological effects; however, their roles in NSCLC metastasis remain unexplored. This study aimed to elucidate the mechanisms by which Loureirin A and Loureirin B suppress EMT, migration, and invasion in NSCLC cells via the MAPK signaling pathway. The sulforhodamine B (SRB) assay showed that Loureirin A and Loureirin B, at concentrations ranging from 0 to 140 μM, were non-toxic to both A549 and H1299 cells. Additionally, Loureirins A and B exhibited no cytotoxic effects on primary human dermal fibroblast cells and did not induce hemolysis in red blood cells (RBCs). The wound-healing and trans-well assays were used to evaluate the anti-migratory and anti-invasion properties of Loureirin A and Loureirin B in NSCLC cell lines. Gelatin zymography was employed to investigate the activity of MMP-2 (gelatinase A) and MMP-9 (gelatinase B), while Western blot analysis was used to examine the expression of EMT markers and invasive proteins, and the phosphorylation of MAPK signaling molecules. Our results demonstrate that both Loureirin A and Loureirin B significantly suppressed the migration and invasion of A549 and H1299 cells. These compounds suppressed the activity of matrix metalloproteinases MMP-2 and MMP-9 and downregulated the expression of key invasive proteins including uPA, uPAR, and MT1-MMP. Additionally, they effectively suppressed the expression of EMT markers such as N-cadherin, Vimentin, and Fibronectin. Mechanistically, Loureirin A and Loureirin B inhibited the MAPK signaling pathway by downregulating the phosphorylation of ERK, JNK, and p38 proteins. In conclusion, these findings demonstrate that Loureirin A and Loureirin B exhibit potent anti-invasive properties and no cytotoxic effect on NSCLC cell lines, suggesting their potential as promising candidates for anti-cancer drug development. Furthermore, they may pave the way for the exploration of combination therapies with other anti-cancer drugs for clinical translation.