The anti-cancer peptides emerged as new weapons for cancer therapy due to their potent toxicity toward various cancer cells. However, their therapeutic promise is often limited by non-specific toxicity to normal cells. How to improve peptides' selectivity to cancer cells is always a matter to solve. In this manuscript, we designed a sulfonium tethered lytic peptide conjugated with a HDAC inhibitor to improve the selectivity of cancer cells. The sulfonium tethered lytic peptide with improved hydrophilicity and positive charge showed reduced toxicity to both cancer cells and normal cells. When conjugated with the HDAC inhibitor, this peptide showed increased toxicity to cancer cells. Besides, the stabilized peptide HDAC conjugate showed better serum stability than the linear peptide conjugate. For cellular function, the stabilized peptide conjugate could induce cancer cell apoptosis, cell cycle arrest, and influence multiple signal pathways through transcriptome analysis. This design may provide an alternative approach for the development of safe and effective anti-cancer drugs.