The miscibility of Chitosan (CS) and poly(ethylene oxide) (PEO) in their blends and the effect of K + and Ca 2+ doping on the CS/PEO interaction have been investigated in this work. CS and PEO appeared to be miscible and the DSC analysis suggested the Flory–Huggins interaction parameter χ AB to be −0.21. Doping of K + and Ca 2+ into the CS/PEO blend matrix enhanced the cooperative interaction between CS and PEO and this enhancement was larger for Ca 2+ than for K + . The difference between Ca 2+ and K + possibly reflects a stronger multi-valence interaction of Ca 2+ with the amino and hydroxyl groups of CS as well as the ether groups of PEO to form a stable CS/Ca 2+ /PEO complex and a less significant interaction of K + , as suggested by DSC, WAXD and FTIR results. MD simulations clearly indicated the correlation between the dynamic behavior and the interaction of K + and Ca 2+ in the CS/PEO blend matrix.