Understanding the magnetic ordering and its connection to unusual physical properties, e.g. high-Tc superconducting, of systems containing the Cu-O-Cu bondings has been an important concern since the 1980s. Here, the counterintuitive negative thermal expansion (NTE) in CuO is explained via electron-transfer-driven spin exchange interactions. The elusive underlying mechanism of how the strong spin-lattice coupling gives rise to the NTE of CuO is investigated by neutron Bragg diffraction and principal axis of strain calculation (PASCal) analysis. Based on the Hubbard model, the density functional theory (DFT) calculations show that as the temperature decreases, the increasing electron transfer fundamentally accounts for the enhancement of the exchange interaction along [101 ̅] – the principal NTE direction. It is further rationalized that only when the interaction along [101 ̅] is preferably enhanced to a certain level compared to the other antiferromagnetically exchange pathways can the corresponding NTE behavior occur. Combined with recently reported research into optical modification of the exchange interaction, outcomes from this work have implications for controlling the thermal expansion behavior through optical manipulation of strong-correlated systems.