Autologous cardiac progenitor cell (hCPC) therapy is a promising alternative approach to current inefficient therapies for heart failure (HF). However, ex vivo expansion and pharmacological/genetic modification of hCPCs are necessary interventions to rejuvenate aged/diseased cells and improve their regenerative capacities. This study was designed to assess the potential of improving hCPC functional capacity by targeting P2Y14 purinergic receptor (P2Y14R), which has been previously reported to induce regenerative and anti‐senescence responses in a variety of experimental models. c‐Kit+ hCPCs were isolated from cardiac biopsies of multiple HF patients undergoing left ventricular assist device (LVAD) implantation surgery. Significant correlations existed between expression of P2Y14R in hCPCs and clinical parameters of HF patients. P2Y14R was downregulated in hCPCs derived from patients with relatively lower ejection fraction and patients diagnosed with diabetes. hCPC lines with lower P2Y14R expression did not respond to P2Y14R agonist UDP‐glucose (UDP‐Glu) while hCPCs with higher P2Y14R expression showed enhanced proliferation in response to UDP‐Glu stimulation. Mechanistically, UDP‐Glu stimulation enhanced activation of canonical growth signalling pathways ERK1/2 and AKT. Restoring P2Y14R expression levels in functionally compromised hCPCs via lentiviral‐mediated overexpression improved proliferation, migration and survival under stress stimuli. Additionally, P2Y14R overexpression reversed senescence‐associated morphology and reduced levels of molecular markers of senescence p16INK4a, p53, p21 and mitochondrial reactive oxygen species (ROS). Findings from this study unveil novel biological roles of the UDP‐sugar receptor P2Y14 in hCPCs and suggest purinergic signalling modulation as a promising strategy to improve phenotypic properties of functionally impaired hCPCs. This article is protected by copyright. All rights reserved