Influence of six metal ions viz. Mg2+, K+, Ca2+, Mn2+, Cu2+ and Ba2+ on the binding affinity of human serum albumin (HSA) towards three antimalarial drugs, namely, sulfadoxine (SDN), mefloquine (MEF) and lumefantrine (LUM) was investigated using fluorescence quenching titrations. The effects of metal ions (Mn2+, Cu2+ and Ba2+) were similar on the affinity of HSA towards SDN, MEF and LUM. Values of the association constant, Ka, for SDN/MEF/LUM ̶ HSA interactions in the presence of these metal ions, decreased significantly in the order: Mn2+ > Cu2+ > Ba2+. On the other hand, the presence of Mg2+, K+, and Ca2+ affected the binding affinity for these drugs differently. Whereas a slight increase in the Ka value of the SDN ̶ HSA complex was seen in the presence of Mg2+, Ca2+ produced a similar effect on the LUM ̶ HSA system. For MEF ̶ HSA and LUM ̶ HSA systems, effects of K+ and Mg2+ were similar, showing a decrease in the Ka value, being more effective with K+; however, this decrease was more significant than Mn2+, Cu2+ and Ba2+. Values of ‘n’ remained approximately equal to 1, hinting at a single binding site for each drug.