Microgels of maltodextrin (MDex) as poly(maltodextrin) (p(MDex)) were prepared by reverse-micelle cross-linking technique at various crosslinking ratios, 25, 50, and 100% based on the repeating unit of MDex using divinylsulfone (DVS) as crosslinker and were designated as p(MDex)-1, p(MDex)-2, and p(MDex)-3 respectively. The prepared p(MDex) microgels were blood compatible with <2% hemolysis and > 80%blood clotting index values at 1.0 mg/mL concentration. Also, p(MDex) microgels were found as biocompatible with >90% cell viability against L929 fibroblast cells at 1.0 mg/mL concentrations. Furthermore, p(MDex)-3 microgels were modified with ethylenediamine (EDA) and pentaethylenehexamine (PEHA) to generate new amine groups on microgels surface to obtain p(MDex)-EDA and p(MDex)-PEHA, respectively to render new surface functionality and features. The drug delivery potentials of p(MDex)-3, p(MDex)-EDA, and p(MDex)-PEHA microgels were tested employing amoxicillin (Amox) for loading and release studies at pH 7.4 and 37 ◦C. Higher drug loading amount, loading content%, and encapsulation efficiency% values were attained for p(MDex)-PEHA microgels with 112.5 ± 9.9 mg/g, 12.8 ± 1.1%, and 63.4 ± 4.1%, respectively. The Amox-loaded p(MDex)-3, p(MDex)- EDA, and p(MDex)-PEHA microgels released 90.8 ± 0.9, 86.2 ± 10.8, and 87.2 ± 9.6% of the loaded Amox at pH 7.4 PBS in 125 h. Controlled and extended drug delivery system at the therapeutic window is of paramount significance in treatment of various diseases. P(MDex)-PEHA microgels revealed almost a linear Amox release profile for up to 28 h. The Amox release from the p(MDex) microgels was fitted with the Korsmeyer-Peppas model with n values <0.5.