A series of sixteen curcumin derivatives (CURC-D) were designed and evaluated for their antibacterial/antifungal activity. POM analyses showed that lipophilicity and presence of (X–Y) pharmacophore site (X, Y = O, N) are the major factors that governed the orientation in determining antibacterial and/antifungal activity. Furthermore, it was also found that some of the POM analyzed CURC-derivatives have a closed pharmacophore sites which might be responsible of low bioactivity. To confirm the electronic, steric, and hydrophobic requirements for future modifications, we have also carried out receptor-based electrostatic analysis. Therefore, we conclude that POM analyses may prove to be a suitable method to correlate structural features of CURC-D with their promising combined antibacterial/antifungal activity and may contribute to the development of novel antimicrobial agents against drug-resistant human pathogens.