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Antibody drug conjugates (ADC) are an emerging class of pharmaceuticals consisting of cytotoxic agents covalently attached to an antibody designed to target a specific cancer cell surface molecule followed by internalization and intracellular release of payload to exhibit its anticancer activity. Targeted delivery of cytotoxic payload to a variety of specific cells has been demonstrated to have significant enhancement in clinical efficacy and dramatic reduction in off‐target toxicity. Site‐specific conjugation of payload to the antibody is highly desirable for development of ADC with well‐defined antibody‐to‐drug ratio, enhanced internalization, reduced toxicity, improved stability, desired pharmacological profile and optimal therapeutic index. Here, we reported a site‐specific conjugation strategy for evaluation of antibody internalization and efficacy of ADC designed to target SSEA4 on solid tumors. This strategy stems from the azido‐fucose tag of a homogeneous antibody Fc‐glycan generated viain vitroglycoengineering approach for site‐specific conjugation and optimization of antibody‐drug ratio to exhibit optimal efficacy. The ADC consisting of a chimeric anti‐SSEA4 antibody chMC813‐70, conjugated to the antineoplastic agent monomethyl auristatin E via both cleavable and non‐cleavable linkers showed excellent cytotoxicity profile towards SSEA4‐bearing cancer cells. A clear distinction in cytotoxicity was observed among cancer cells with different SSEA4 expression levels.