The cross-linking effect of the hydrophobic cores on the morphology of giant vesicles was explored using amphiphilic poly(methacrylic acid)-block-poly(methyl methacrylate-random-methacrylic acid), PMAA-b-P(MMA-r-MAA), and ethylene glycol dimethacrylate (EGMA) as the cross-linking agent. Spherical vesicles without cross-linking were transformed into large contorted vesicles with a rough surface by the cross-linking of the P(MMA-r-MAA) blocks with EGMA. An increase in the EGMA ratio promoted a further transformation into huge spherical particles with a smooth surface, followed by smaller partly joined particles. A still higher EGMA ratio caused the joining of particles along with a further decrease in the particle size. The cross-linking of the hydrophobic blocks also dominated the crystallization of the hydrophilic PMAA blocks. The thermal analysis demonstrated that the glass transition temperature of the PMAA blocks increased with the EGMA ratio for the identical PMAA block length. The crystallinity of the hydrophobic cores enhanced that of the hydrophilic surface.