A comprehensive approach is proposed for system design and analysis of polymer-based optical interconnects (OIs) on FR4 substrate for electro-optical printed circuit boards (EOPCB) to enable high-speed data transfer exceeding 10 Gbps. The design approach is based on achieving vertical coupling of light from the external light source into the waveguides in the optical layer. Prior component-level design and analysis are accomplished, followed by system-level study and further sensitivity analysis. The main building block of the optical layer for light transmission is the optical waveguides, which are designed and optimized in terms of core and cladding dimensions, core-cladding polymer materials, sidewall roughness, bend radius, and the transmitting source’s divergence and misalignment. Based on the simulation studies, various design rules are defined. The designed optical interconnect meets the system-level bit error rate (BER) requirement of 10−12. System-level Monte Carlo analysis shows that the achieved BER performance is optimum within the statistical Gaussian variation of the input design parameters. Finally, the sensitivity of the BER performance is studied against a 10% variation in the input design parameters. The proposed approach can significantly help in the system design and analysis of OIs for EOPCBs.