Background: ??-hemoglobinopathies are one of the most common recessive genetic diseases worldwide, with limited treatments available, particularly in developed countries where the prevalence is higher. Pharmacological reactivation of Fetal Hemoglobin (HbF) is a promising therapeutic strategy. However, approximately 25% of the patients do not respond to Hydroxyurea (HU), the first and most commonly used HbF inducing agent approved by the FDA. Objective: Here, we performed an in vitro assessment of transcriptional effects induced by natural bioactive compounds, namely Epigallocatechin-3-gallate (EGCG) and genistein (GN) in globin genes (HBA1, HBB, HBG1 and HBG2) in HbF regulators/silencer genes (KLF1, BCL11A, MYB and BGLT3) and in epigenetic regulator genes (DNMT1, DNMT3A, DNMT3B, HDAC1, HDAC2, HDAC3 and HDAC8). Moreover, we evaluated EGCG’s in vivo effects in hematological parameters of healthy volunteers. Methods: K562 cells were exposed for 72 and 96 h to GN and EGCG at 100, 250 and 500 ng/mL. Cell proliferation and viability were measured, and transcriptional levels were evaluated by qRT-PCR. For in vivo assay, complete blood count was determined by flow cytometry and HbF level was determined through HPLC in 30 healthy individuals before and after 225 mg EGCG ingestion per day during a 90-day period. Results: Both compounds impact cellular metabolism and proliferation with no cytotoxic effects. Divergent GN and EGCG effects in globin and BGLT3 expression levels suggest the involvement of divergent signaling pathways. As for the epigenetic potential, EGCG particularly affects HDAC2 and HDAC8 transcription, whereas GN signifi-cantly affects expression patterns of methylation and acetylation modulators. HU appears to have time divergent effects, with greater impact in methylation at 72 h (overregulates DNTM3A) while affecting acetylation mostly at 96 h (downregulates HDAC1 and HDAC8). Additionally, in vivo, EGCG demonstrated a modulator effect in hematopoiesis and HbF induction. Conclusion: Our results advocate EGCG and GN with HbF pharmacological reactivation potential and sustain further research as new alternative approaches for ??-hemoglobinopathies therapies.