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Tanning response and melanocyte differentiation are mediated by the central transcription factor MITF. This involves the rapid and selective induction of melanocyte maturation genes, while concomitantly the expression of other effector genes is maintained. In this study, using cell‐based and zebrafish model systems, we report on a pH‐mediated feed‐forward mechanism of epigenetic regulation that enables selective amplification of the melanocyte maturation program. We demonstrate that MITF activation directly elevates the expression of the enzyme carbonic anhydrase 14 (CA14). Nuclear localization of CA14 leads to an increase of the intracellular pH, resulting in the activation of the histone acetyl transferase p300/CBP. In turn, enhanced H3K27 histone acetylation at selected differentiation genes facilitates their amplified expression via MITF. CRISPR‐mediated targeted missense mutation of CA14 in zebrafish results in the formation of immature acidic melanocytes with decreased pigmentation, establishing a central role for this mechanism during melanocyte differentiation in vivo. Thus, we describe an epigenetic control system via pH modulation that reinforces cell fate determination by altering chromatin dynamics. Synopsis: Melanocyte differentiation is mediated by the transcription factor MITF. A feed‐forward loop involving MITF and the carbonic anhydrase 14 enables the rapid and selective expression of pigmentation genes via pH‐dependent epigenetic marks. The expression of carbonic anhydrase 14 (CA14) is positively regulated by the transcription factor MITF.Nuclear localization of CA14 elevates intracellular pH, which activates p300 and increases H3K27ac at MITF targets.Increased H3K27 acetylation promotes the expression of MITF‐dependent pigmentation genes. [ABSTRACT FROM AUTHOR]