Cytosolic crowding can influence the thermodynamics and kinetics of in vivo chemical reactions. Most significantly, proteins and nucleic acid crowders reduce the accessible volume fraction, ϕ, available to a diffusing substrate, thereby reducing its effective diffusion rate, Deff, relative to its rate in bulk solution. However, Deff can be further hindered or even enhanced, when long-range crowder/diffuser interactions are significant. To probe these effects, we numerically estimated Deff values for small, charged molecules in representative, cytosolic protein lattices up to 0.1 × 0.1 × 0.1 μm(3) in volume via the homogenized Smoluchowski electro-diffusion equation. We further validated our predictions against Deff estimates from ϕ-dependent analytical relationships, such as the Maxwell-Garnett (MG) bound, as well as explicit solutions of the time-dependent electro-diffusion equation. We find that in typical, moderately crowded cell cytoplasm (ϕ ≈ 0.8), Deff is primarily determined by ϕ; in other words, diverse protein shapes and heterogeneous distributions only modestly impact Deff. However, electrostatic interactions between diffusers and crowders, particularly at low electrolyte ionic strengths, can substantially modulate Deff. These findings help delineate the extent that cytoplasmic crowders influence small molecule diffusion, which ultimately may shape the efficiency and timing of intracellular signaling pathways. More generally, the quantitative agreement between computationally expensive solutions of the time-dependent electro-diffusion equation and its comparatively cheaper homogenized form suggest that the latter is a broadly effective model for diffusion in wide-ranging, crowded biological media.