Herein, a series of vitamin E-based TPGS-poly(2-(dimethylamino)ethyl methacrylate)-b-poly(3-vinyl benzaldehyde) block copolymer micelles were synthesized via reversible addition−fragmentation chain-transfer polymerization (RAFT). d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) is a good candidate to overcome the big problem of multidrug resistance in cancer therapy because TPGS can inhibit permeability of glycoprotein (P-gp) resulting in restored sensitivity to chemotherapeutics. Doxorubicin (DOX) was loaded within the micelles, as an anticancer model drug, via hydrolytic amide linkage in the hydrophobic block. The DOX-loaded micelles demonstrated high potential as anticancer drug delivery systems through the release of the drug under acidic conditions, varying from pH 7.4 to 5.0. Three different micelles compositions were investigated with various ratios of hydrophilic and hydrophobic blocks (1:1, 4:3, and 4:1). The DOX-conjugated polymer with the shortest hydrophobic segment (4:1), TPGS-poly(2-(dimethylamino)ethyl methacrylate)125-b-poly(3-vinyl benzaldehyde)91, demonstrated excellent in vitro cytotoxicity with pH-responsive characteristics in comparison to free DOX. Although the higher degree of polymerization of the hydrophobic block promoted the drug loading efficiency of the micelles these compositions demonstrated lower cytotoxicity to the A549 cell line of human lung adenocarcinoma. It was concluded that the prepared pH-responsive micelles based on TPGS are promising drug carriers for anticancer drug delivery systems and could be considered to provide multi-drug resistance cancer treatments after further in vitro biological studies.