DNA damage is one of the key processes that underlie hepatic fibrosis, and its progression could lead to the development of neoplastic events and ultimately hepatocarcinoma. Tissue injury, including DNA damage, can involve the activation of purinergic signaling. It has been shown that P2Y2 receptor signaling is exacerbated during hepatic fibrosis. Little is known, however, about the roles played by P2Y2 receptor in the processes involved in fibrosis. In this study, we used CCl4 treatment to induce a reversible hepatic fibrosis, and by using a microarray assay we observed an upregulation of transcripts related to the DNA damage repair of double strand breaks (DNA-dr-dsb) after P2Y2 receptor stimulation in primary cultures of hepatocytes from fibrotic mice. The transcriptional data were confirmed demonstrating an UTP-promoted reduction in the number of γH2AX+ positive cells in etoposide-treated fibrotic primary hepatocytes. Furthermore, HIF-1α, a known transcription factor that drives P2Y2 receptor expression, showed a significant increase upon CCl4 treatment, especially within the perivascular zones. Chemical activation of HIF-1α by CoCl2 in fibrotic hepatocytes promoted a partial protection against increased levels of γH2AX induced by etoposide, as well as an evident enhancement in the intracellular calcium response induced by UTP in fibrotic hepatocytes, suggesting a regulatory role of this transcriptional factor on the effect of P2Y2 receptor on DNA-dr-dbs response. This regulation was also investigated pharmacologically by activating or blocking the signaling from either P2Y2 receptor or HIF-1α. Our work, in summary, shows a novel relationship between P2Y2 receptor-dependent purinergic signaling and DNA-dr-dbs in hepatic fibrosis.