Hydrolytic reaction of polymers influences the interfacial bonding of cement-polymer composites. The interfacial deterioration mechanism of the calcium silicate hydrates (C–S–H) incorporated by multi-layered Polyacrylamides (PAM) is revealed by molecular dynamics (MD) simulation. To consider the influence of hydrolysis reaction, the amide groups (CONH) of PAM is transformed to deprotonated carboxyl groups (–COO) with the substituted ratio of 100% (fully hydrolysis (FH)), 75% (higher hydrolysis degree (HH)) and 50% (lower hydrolysis degree (LH)). Simulation results reveal that the interfacial chemical bonds are mainly attributed to Ca-O bonds, that is the calcium atoms play a predominated role in connecting with the silicate chains and oxygen-containing functional groups in PAM. Also, in the interior region of multi-layers polymers, hydrolytic reaction can transform the weak H-bonds connection to stable ionic bond connection, which strengthens the inter-polymer network at a high hydrolytic degree. Furthermore, uniaxial tensile modeling results exhibit that the failure mode is greatly dependent on hydrolytic degree for C–S–H/PAM composites. The hydrolytic reaction of PAM not only strengthens interfacial strength but also enhance the ductility of C–S–H/PAM composites. While at a low hydrolytic degree, the composite is stretched to fracture in the interior region of PAM polymers, failure happens at the interface of C–S–H and PAM at a high hydrolytic state. The properties of C–S–H/PAM composites decoded at the atomic scale level might guide the organic–inorganic composites with enhanced mechanical properties and durability.