The unrivaled structural tunability of organic semiconductors allows to tailor their chemical and physical properties for distinct optoelectronic applications. This is particularly true for push-pull conjugated polymers, in which the (hetero)aromatic monomers, substituents, and side chains can be readily adapted. On the other hand, the impact of isomerization within the polymer backbone remains poorly explored. Here, a novel structural isomer of the state-of-the-art push-pull copolymer D18 is synthesized. This ‘isoD18’ regioisomer shows significantly different optical and electrochemical properties. Its deeper highest occupied molecular orbital energy level and reduced non-radiative voltage losses afford a higher open-circuit voltage (from 0.86 to 0.92 V) for the resulting polymer solar cells. Unfortunately, this is accompanied by a decrease in the short-circuit current density and fill factor, which can mainly be attributed to the one-order-lower hole mobility of isoD18, in line with its reduced thin-film organization. Although the performance of the devices based on the isomeric derivative turns out to be lower in this case, this study does enhance our insights into the effects of regioisomerism in polymer semiconductors on the resulting optoelectronic material and device features.