The role of secreted molecules in cellular reprogramming has been poorly understood. Here we identify a truncated form of ephrin receptor A7 (EPHA7) as a key regulator of reprogramming. Truncated EPHA7 is prominently upregulated and secreted during reprogramming. EPHA7 expression is directly regulated by OCT3/4. EphA7 knockdown results in marked reduction of reprogramming efficiency, and the addition of truncated EPHA7 is able to restore it. ERK activity is markedly reduced during reprogramming, and the secreted, truncated EPHA7 is responsible for ERK activity reduction. Remarkably, treatment of EphA7-knockdown MEFs with the ERK pathway inhibitor restores reprogramming efficiency. Analyses show that truncated EPHA7-induced ERK activity reduction plays an important role in the middle phase of reprogramming. Thus, our findings uncover the importance of secreted EPHA7-induced ERK activity reduction in reprogramming.