With recent findings revealing significant micro and nanoplastic (MNPL) concentrations in human blood samples, MNPLs have emerged as a topic of pertinence due to their cytotoxicity. In various gastrointestinal and pulmonary cells, polystyrene microbeads have been evidenced to prompt membrane depolarization and trigger cellular apoptosis, with adversariality varying by MNPL concentration, size of plastic, and presence of surface modifications. Surface modifications in particular, such as amine functionalization (R-NH2), have been qualitatively observed to enhance cellular uptake and thereby toxicity in gastrointestinal cells, while modifications such as carboxylation (R-COOH) impede uptake. However, few computational models address the effects on uptake and likelihood of surface modifications in different plastics. This paper utilizes Frontier Molecular Orbital Theory to predict likely reactions between plastic types and common reagents. Accordingly, among 9 plastic types, ethylene propylene diene and polypropylene polymers were the most reactive and likely to acquire surface modifications. Next, to examine reaction plausibility, retrosynthetic simulations with certain parameters revealed over 30 plausible sequences for each type of carboxyl and amine functionalization for polypropylene and only 1 plausible sequence for each modification of ethylene propylene diene. Finally, to validate the qualitative findings regarding uptake, transmembrane motion of polypropylene with different functionalizations was modeled using computationally determined polypropylene pKa values–9.9 and 45.6 for carboxylated and aminated polypropylene, respectively–and a Henderson-Hasselbach drug migration model. This model confirmed that carboxylation impedes cellular uptake while amine functionalizations enhance uptake in various gastrointestinal environments, ranging in pH from 5.7 to 7.4.