Modulation of existing drugs is required to achieve enhanced activity for cancer therapy by lowering their effective dose. Strategies of introduction of cationic charge and hydrophobicity have been proposed and explored to enhance therapeutic effects of anticancer drugs. In this manuscript, we designed modulation of tamoxifen and synthesized eight tamoxifen (Tam) conjugated lithocholic acid (LCA) amphiphiles with variable cationic charged head groups. We unraveled anticancer potential of these amphiphiles against different breast cancer cell lines. Activity of these amphiphiles is contingent on nature of the charged head group, as hard-charged amphiphiles perform strong membrane interactions and enhanced anticancer activity as compared to soft-charged amphiphiles. In-depth mechanistic studies concluded that conjugation of dimethyl amino pyridine (DMAP) charged head group in case of LCA-Tam-DMAP enhances therapeutic effect of Tam in breast cancer cells, and makes it highly effective even against ER negative cells. Amphiphilic character of these lipid-drug conjugates can further be explored for engineering of nanotherapeutics for targeting tumors. Therefore, fine-tuning the interactions of drugs with cell membranes can help in engineering of future lipid-drug conjugates for effective cancer therapy.