FOXH1 is a primitive-streak specifier and ACTIVIN co-effector that plays an important role in development, and positively regulates the generation of human induced pluripotent stem cells (iPSCs) from somatic cells by OCT4, SOX2, KLF4, and MYC (OSKM) transduction. However, the mechanism and upstream regulation for FOXH1 expression in reprogramming are unclear. We found FOXH1 expression plays a significant role to enhance epithelial marker and suppress mesenchymal gene expression in OSKM-mediated human cell reprogramming. Furthermore, NANOG and LIN28 (NL) co-stimulate FOXH1 expression, which correlates with the enhanced reprogramming efficiency by NL-factors. FOXH1 expression is also stimulated by a specific inhibitor for H3K79 methyltransferase DOT1L (iDOT1L) but not by inhibition of the canonical WNT signaling. We further show that blocking endogenous FOXH1 expression eliminates the enhanced reprogramming effect by NL and iDOT1L. However, overexpressing FOXH1 in NL plus iDOT1L condition results in significantly reduced TRA-1-60 positively expressed cells and decreases pluripotent marker expression in reprogramming. Our study elucidated an essential role for properly stimulated FOXH1 expression by NANOG, LIN28, and H3K79 demethylation for dramatic enhancement of reprograming.