Finite-difference time-domain (FDTD) electromagnetic simulations are a computational method that has seen much success in the study of biological optics; however, such simulations are often hindered by the difficulty of faithfully replicating complex biological microstructures in the simulation space. Recently, we designed simulations to calculate the trajectory of electromagnetic light waves through realistically reconstructed retinal photoreceptors and found that cone photoreceptor mitochondria play a substantial role in shaping incoming light. In addition to vision research and ophthalmology, such simulations are broadly applicable to studies of the interaction of electromagnetic radiation with biological tissue. Here, we present our method for discretizing complex 3D models of cellular structures for use in FDTD simulations using MEEP, the MIT Electromagnetic Equation Propagation software, including subpixel smoothing at mesh boundaries. Such models can originate from experimental imaging or be constructed by hand. We also include sample code for use in MEEP. Implementation of this algorithm in new code requires understanding of 3D mathematics and may require several weeks of effort, whereas use of our sample code requires knowledge of MEEP and C++ and may take up to a few hours to prepare a model of interest for 3D FDTD simulation. In all cases, access to a facility supercomputer with parallel processing capabilities is recommended. This protocol offers a practical solution to a significant challenge in the field of computational electrodynamics and paves the way for future advancements in the study of light interaction with biological structures.