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The interaction between hyaluronan and CD44, an important cancer stem‐cell marker, stimulates various tumor cell‐specific functions such as the stemness of tumor cells. microRNA‐203 (miR‐203) can be downregulated by this interaction in human colorectal cancer (CRC) cells, which increases their stemness; however, the underlying mechanism is not yet defined. Here, we show that overexpression and sequestration of miR‐203 in HCT‐116 and HT‐29 human CRC cells reduces and enhances their stemness, respectively. We also show that GATA‐binding factor 6 (GATA6) is a direct target of miR‐203. Our results indicate that upregulated expression of this transcription factor not only restores the self‐renewal abilities of miR‐203‐overexpressing HCT‐116 and HT‐29 cells but also promotes the stemness properties of their parental counterparts. More important, we show that silencing the expression of either LRH‐1 or Hes‐1 is sufficient to diminish the stemness‐promoting effects of GATA6 in human CRC cells. Together, our findings delineate the stemness‐inhibitory mechanism of miR‐203 in human CRC cells and suggest that this miR is a potential therapeutic agent for colorectal cancer. [ABSTRACT FROM AUTHOR]