There has been significant interest in designing heterostructured nanoparticles with excellent synergistic properties and multifunctionality. Herein, this work reports on the design of reactive oxygen species- (ROS-) responsive Ag decorated TiO2 hybrid nanorods (HNRs) with dual functionalities of enhanced photodynamic therapy and antibacterial activity. A de-wetting phenomenon was employed to nucleate and crystallize Ag nanoparticles onto the surface of TiO2 nanorods resulting in Ag-TiO2 hybrid nanocomposites. The use of the Pluronic® F-127 polymer, which is permitted by the Food and Drug Administration (FDA), remarkably improved the biocompatibility of Ag-TiO2 HNRs tested in 4T1 breast cancer cells. Furthermore, Ag-TiO2 HNRs endocytosed by cancer cells produced high intracellular ROS under UV conditions (5.6 mW cm−2), resulting in cancer cell apoptosis. Similarly, the distinctive features of Ag NPs on TiO2 nanorods slow down the recombination rate of electrons–holes, and exhibited 90% killing efficacy against Escherichia coli (gram-negative/rods) and Staphylococcus aureus (gram-positive/cocci). The potential of photo-activated Ag-TiO2 HNRs, as demonstrated in this work, indicates that this heterostructured material is a promising novel dual-therapeutic strategy against cancer cells and microbial agents.