Reducing non-radiative recombination energy loss (ΔEnonrad) in organic solar cells (OSCs) has been considered an effective method to improve device efficiency. In this study, the backbone of PTBTT-4F/4Cl is divided into D1-D2-D3 segments and reconstructed. The isomerized TPBTT-4F/4Cl obtains stronger intramolecular charge transfer (ICT), thus leading to elevated highest occupied molecular orbital (HOMO) energy level and reduced bandgap (Eg). According to ELoss = Eg–qVOC, the reduced Eg and enhanced open circuit voltage (VOC) result in lower ELoss, indicating that ELoss has been effectively suppressed in the TPBTT-4F/4Cl based devices. Furthermore, compared to PTBTT derivatives, the isomeric TPBTT derivatives exhibit more planar molecular structure and closer intermolecular stacking, thus affording higher crystallinity of the neat films. Therefore, the reduced energy disorder and corresponding lower Urbach energy (Eu) of the TPBTT-4F/4Cl blend films lead to low ELoss and high charge-carrier mobility of the devices. As a result, benefitting from synergetic control of molecular stacking and energetic offsets, a maximum power conversion efficiency (PCE) of 15.72% is realized from TPBTT-4F based devices, along with a reduced ΔEnonrad of 0.276 eV. This work demonstrates a rational method of suppressing VOC loss and improving the device performance through molecular design engineering by core segmentation and isomerization.