Background: Eucheuma cottonii (EC) is a rapidly growing red seaweed in Southeast Asia. Objectives: This study was performed to investigate the effects of EC extract on human keratinocyte migration. Materials and Methods: Cell migration was assessed using the scratch wound assay. Western blot analysis was performed to investigate the EC extract-induced signaling pathways. Results: EC extract promoted HaCaT keratinocyte migration in a concentration-dependent manner. To investigate the mechanism of EC extract-induced migration, we examined the migration-related signaling pathways. Western blot analysis showed that the EC extract showed no changes in extracellular signal-activated kinase (ERK) but showed slight Akt activation. In contrast, the EC extract strongly phosphorylated p38 mitogen-activated protein kinase (MAPK) and the subsequent downstream molecule, cAMP response element-binding protein (CREB). To examine the involvement of p38 MAPK pathway in EC extract-induced migration, SB203580, a specific inhibitor of p38 MAPK, was used. The results showed that EC extract-induced migration was abrogated by SB203580 pretreatment. In addition, SB203580 also blocked p38 MAPK and CREB activation. Conclusion: Taken together, these data suggest that EC extract promotes migration in human keratinocytes via p38 MAPK and CREB phosphorylation.