This article presents a thermodynamic model to understand the size-dependent endocytosis of ligand-coated nanoparticles (NPs) in biological cells. The model identifies three regimes based on the NP radius: a regime where endocytosis is minimal (R < Rmin ≈ 22 nm), a regime where endocytosis is rare (R > Rmax ≈ 60 nm), and an optimal regime (Rmin < R < Rmax) where the cellular uptake is maximized. The optimal NP radius is found to be around 25–30 nm, which aligns with experimental observations. The model also shows that the cellular uptake is regulated by membrane tension and surface concentration of NPs. At the optimal radius, the cellular uptake reaches a maximum of several thousand, and the model's predictions are consistent with experimental data. The study provides insights into the design of NP-based drug delivery systems and bioimaging applications.This article presents a thermodynamic model to understand the size-dependent endocytosis of ligand-coated nanoparticles (NPs) in biological cells. The model identifies three regimes based on the NP radius: a regime where endocytosis is minimal (R < Rmin ≈ 22 nm), a regime where endocytosis is rare (R > Rmax ≈ 60 nm), and an optimal regime (Rmin < R < Rmax) where the cellular uptake is maximized. The optimal NP radius is found to be around 25–30 nm, which aligns with experimental observations. The model also shows that the cellular uptake is regulated by membrane tension and surface concentration of NPs. At the optimal radius, the cellular uptake reaches a maximum of several thousand, and the model's predictions are consistent with experimental data. The study provides insights into the design of NP-based drug delivery systems and bioimaging applications.