Fish exhibit a wide range of sex determination mechanisms, coupled with a high turnover of master sex-determining genes. As a result, the downstream molecular pathways and regulations governing sex determination and differentiation have undergone iterative adaptations over the course of evolution. Interestingly, various members of the TGF-β family (including Amh, Gsdf, Gdf6, Bmpr1bb, Amhr2…) have played pivotal roles in the emergence of most sex-determining genes in fish. Focusing on the functions of Gdf6 to potentially unveil new conserved mechanisms regulating sex determination, we discovered that the medaka GDF6 paralogs control gonadal commitment in an (unforeseen) heritable epigenetic manner. Hence, while GDF6 CRISPR/Cas9-mediated knockout fish undergo XY male-to-female sex reversal, we demonstrated that this sex reversal is indeed correlated with profound rearrangements in the entire epigenetic landscape, including the hypermethylation of parts of the Y chromosome, leading to the inactivation of the master sex-determining gene (Dmrt1bY) in medaka. Further investigations established that XY male-to-female sex reversal occurs only when: i) the gamete carrying the mutation also carries the Y chromosome, or when ii) independently of the GDF6 mutation, the Y chromosome is inherited from an already sex-reversed XY female. Most importantly, this phenomenon of transgenerational sex reversal is abolished when embryos are either treated with the DNA demethylating compound 5-azacytidine or subjected to targeted CRISPR-dCas9-TET1 epigenetic editing. This suggests that the sex-reversal process might be driven and transmitted through epigenetic alterations. In accordance with these findings, overexpression of GDF6b in a medaka cell line results in the nuclear-to-cytoplasmic delocalization of DNMT1 and UHRF1 proteins, two key factors known to be involved in the maintenance of the whole DNA methylation landscape. Finally, transcriptomic analyses suggest that GDF6-induced epigenetic imprinting could be mediated in an original way by a phylogenetically conserved family of transcription factors. Taken together, our data strongly support the idea that GDF6 signalling, uniquely transmitted through gametes in a transgenerational and persistent manner, is physiologically integrated by safeguarding the methylation states of various loci within the genome, ultimately influencing sex determination.