Organic photovoltaics based on polymer blends have the potential for flexible solar cells with superior mechanical and thermal resiliency. Recently, regioregular polymerized small molecule acceptors (PSMAs) were synthesized and utilized as active acceptor materials to achieve record-breaking all-polymer solar cells with power conversion efficiency approaching 20%. The reported experimental studies show a systematic correlation between polymerization sites and the properties of the PSMA, where one of the regioisomers (γ-PSMA) displays more favorable optoelectronic and photovoltaic properties compared to the other (δ-PSMA). However, these experimental observations have not yet been rationalized. Here, we used first-principles calculations to reveal that the substituents on the cross-conjugated terminal unit of the SMA core are responsible for improving the optoelectronic properties of γ-PSMAs, by extending the conjugation length and enhancing favorable mesomeric effects. Importantly, we demonstrate that these effects can be exploited as a universal molecular design principle, and we predict that functionalizing PSMAs in selected positions with electron-withdrawing groups can further improve their optoelectronic properties. Our study provides a quantitative framework for understanding and rationalizing the relationship between polymerization sites and optoelectronic properties in regioregular PSMAs; in addition, our results pave the way for a rational design principle to further improve the properties of these conjugated polymers and, in turn, the efficiency of all-polymer solar cells.