Organic Photovoltaic Cells (OPVCs), having received significant attention over the last decade, are yet to be established as viable alternatives to conventional solar cells due to their low power conversion efficiency (PCE). Complex interactions of several phenomena coupled with the lack of understanding regarding the influence of fabrication conditions and nanostructure morphology have been major barriers to realizing higher PCE. To this end, we propose a computational microstructural design framework addressing the Processing–Structure–Performance (PSP) linkages for designing the active layer of P3HT:PCBM based OPVCs conforming to bulk heterojunction architecture. The framework pivots around the Spectral Density Function (SDF), a frequency space microstructure characterization and reconstruction methodology, for microstructure design representation. Nanostructure images obtained by novel Scanning Tunneling Microscopy are used to validate the applicability of SDF for representing active layer morphology in OPVCs. SDF enables a low dimensional microstructure representation that is crucial in formulating a parametrized microstructure optimization scheme. A level-cut Gaussian Random Field (governed by SDF) technique is used to generate reconstructions that serve as Representative Volume Elements (RVEs) for structure-performance simulations. A novel structure-performance simulation approach is developed using physics-based performance metric, Incident Photon to Converted Electron (IPCE) ratio, to account for the impact of microstructural features on OPVC performance. Finally, an SDF based computational IPCE optimization study using metamodels created using design of computer experiments over three design variables results in 36.75% increase in IPCE, underlining the efficacy of proposed design framework.