A series of pH-responsive amphiphilic conetworks (APCNs) were synthesized through cross-linking of well-defined amphiphilic pentablock copolymers via atom transfer radical polymerization (ATRP). A new ditelechelic polydimethylsiloxane macroinitiator was synthesized to initiate the polymerization of N,N-dimethylaminoethyl methacrylate. The resulting triblock copolymers showed well-defined molecular weight with narrow polydisperisty, which were used as macroinitiator to incorporate allyl methacrylate to get the pentablock copolymers with allyl pendant groups. Then, pentablock copolymers were fully cross-linked with polyhydrosiloxanes through hydrosilylation. The so-prepared APCNs exhibited unique properties of microphase separation of hydrophilic (HI) and hydrophobic (HO) phases with small channel size, a variable swelling capacity in media with different pH and polarity, a good mechanical property (1.3 ± 0.2 MPa) and outstanding oxygen permeability (300 ± 120 barrers). The properties of APCNs depend on the ratio of HI–HO, which can be regulated via precise synthesis of the triblock copolymers. The APCNs showed well-controlled drug release to Rhodamine 6G upon varying the pH. Meanwhile, the controlled manner is also attributed to the well-defined molecular structure and tunable HI/HO composition of the APCNs.