Well-defined, semi-degradable polyester/polymethacrylate block copolymers, based on ε-caprolactone (CL), d,l-lactide (DLLA), glycolide (GA) and N,N′-dimethylaminoethyl methacrylate (DMAEMA), were synthesized by ring-opening polymerization (ROP) and atom transfer radical polymerization. Comprehensive degradation studies of poly(ε-caprolactone)-block-poly(N,N′-dimethylaminoethyl methacrylate) (PCL-b-PDMAEMA) on hydrolytic degradation and enzymatic degradation were performed, and those results were compared with the corresponding aliphatic polyester (PCL). The solution pH did not affect the hydrolytic degradation rate of PCL (a 3% Mn loss after six weeks). The presence of a PDMAEMA component in the copolymer chain increased the hydrolysis rates and depended on the solution pH, as PCL-b-PDMAEMA degraded faster in an acidic environment (36% Mn loss determined) than in a slightly alkaline environment (27% Mn loss). Enzymatic degradation of PCL-b-PDMAEMA, poly(d,l-lactide)-block-poly(N,N′-dimethylaminoethyl methacrylate) (PLA-b-PDMAEMA) and poly(lactide-co-glycolide-co-ε-caprolactone)-block-poly(N,N′-dimethylaminoethyl methacrylate) (PLGC-b-PDMAEMA) and the corresponding aliphatic polyesters (PCL, PLA and PLGC) was performed by Novozyme 435. In enzymatic degradation, PLGC degraded almost completely after eleven days. For polyester-b-PDMAEMA copolymers, enzymatic degradation primarily involved the ester bonds in PDMAEMA side chains, and the rate of polyester degradation decreased with the increase in the chain length of PDMAEMA. Amphiphilic copolymers might be used for biomaterials with long-term or midterm applications such as nanoscale drug delivery systems with tunable degradation kinetics.