This paper addresses the optimization of the interface between the photodetector (PD) and the analog frontend (AFE) in high-speed, high-density optical communication receivers. Specifically, the paper focuses on optimizing design elements in the interface, including the interconnecting transmission line, the T-coil, the transimpedance amplifier (TIA), and digital equalization tap weights. To optimize the optical link, we use a combination of analytical models, electromagnetic simulations (EM), and machine learning (ML) techniques to describe different interface elements as most appropriate for each. Finally, we use the genetic algorithm to obtain optimal design parameters. The proposed optimization approach leads to a quick design time and reveals insights into some of the best design practices. As an example, we use the proposed method to investigate the relationship between optimal transmission line width and the amount of equalization available on the receiver. These conclusions are further supported by measurements taken on an assembled prototype with various PD-to-TIA interconnect lengths.