Magneto-plasmonic nanoparticles (MPNPs), such as solid gold (Au) or hollow gold (HG) coated superparamagnetic iron oxide (SPIO) nanoparticles (NPs), have attracted increasing attention for brain-targeted therapeutics. This is due to their supreme magnetic targeting capability, light-to-heat conversion efficiency, and biocompatibility. Though promising, their therapeutic efficiency is difficult to predict because of the complex absorption, distribution, metabolism, and excretion process and the intrinsic and extrinsic properties of the blood–brain barrier (BBB). This paper presents a modern physiologically based pharmacokinetic (PBPK) model to predict pharmacokinetic (PK) behaviors of brain-targeting MPNPs and investigate their morphology and surface function-dependent BBB crossing efficiency. This model quantifies intrinsic and extrinsic properties of PK parameters, including phagocytic cellular uptake rate and brain permeability. This model successfully predicts the biodistribution of functionalized Au-SPIO (18.42 ± 0.23 nm) and HG-SPIO (73.65 ± 1.46 nm) MPNPs in 8-week-old adult mice in a 16-h window after intraperitoneal (IP) injection. These predictions agree well with the experimental data with a low absolute average fold error (1.5381 for Au-SPIO and 1.1225 for HG-SPIO NPs). Interestingly, Au-SPIO MPNPs with thinner plasmonic layers result in higher magnetization levels and thus lead to more efficient BBB crossing. Static magnetic field stimulation could improve brain accumulation of IP-injected Au-SPIO and HG-SPIO NPs by up to 4.9% and 1.4%, respectively. Additionally, IP injection led to higher brain accumulation compared to intravenous injection. This modern PBPK model can guide MPNP design optimization for brain-specific therapeutics.