Despite epithelial acid-base regulatory abilities described for cephalopods, the evo-devo basis for extracellular pH homeostasis is still poorly understood in these non-model organisms. In this study expressions of epidermal morphogenesis marker (ΔNp63) and neurohypophysial hormone (sepiatocin) receptors were examined by using embryos of cuttlefishSepia pharaonis. Using CO2 perturbation experiments, key players of epithelial acid-base regulation in different ontogenetic stages, including V-type H+-ATPase (VHA), Na+/HCO3- co-transporter (NBC), Na+/H+ exchanger3 (NHE3), Rhesus protein (RhP) and Na+/H+ exchanger3 (NHE3) as well as ΔNp63 and sepiatocin receptor 2 (str2) were apparently affected by ambient hypercapnic challenges.Those transcripts expressions inferred that the activations of ΔNp63 and STR2 might be involved in operating epidermal ion fluxes. Moreover in situ hybridization images showed that both ΔNp63 and STR2 were expressed on epithelium and gills in embryos of S. pharaonis supporting the central sites of acid-base regulatory mechanism. The present work suggests that in convergence to teleosts, cephalopod embryos have evolved sophisticated evolution pathway regarding epithelium differentiation and neurohypophysial hormones regulation to cope with acid-base disturbances during their oviparous development.