Antibacterial treatment strategies using functional nanomaterials, such as photodynamic therapy, are urgently required to combat persistent small colony variant (SCV) bacteria. Using a stepwise approach involving thermolysis to form β-NaYF:Yb/Tm upconversion nanoparticles (UCNPs) and surface ligand exchange with cetyltrimethylammonium bromide (CTAB), followed by zeolite imidazolate framework-8 (ZIF-8) coating and conversion to zinc oxide (ZnO), β-NaYF:Yb/Tm@ZnO nanoparticles were synthesized. The direct synthesis of β-NaYF:Yb/Tm@ZIF-8 UCNPs proved problematic due to the hydrophobic nature of the as-synthesized material, which was shown by zeta potential measurements using dynamic light scattering (DLS). To facilitate deposition of a ZnO coating, the zeta potentials of (i) as-synthesized UCNPs, (ii) calcined UCNPs, (iii) polyvinylpyrrolidone (PVP), and (iv) CTAB-coated UCNPs were measured, which revealed the CTAB-coated UCNPs to be the most hydrophilic and the better-dispersed form in water. β-NaYF:Yb/Tm@ZIF-8 composites formed using the CTAB-coated UCNPs were then converted into β-NaYF:Yb/Tm@ZnO nanoparticles by calcination under carefully controlled conditions. Photoluminescence analysis confirmed the upconversion process for the UCNP core, which allows the β-NaYF:Yb/Tm@ZnO nanoparticles to photogenerate reactive oxygen species (ROS) when activated by near-infrared (NIR) radiation. The NIR-activated UCNPs@ZnO nanoparticles demonstrated potent efficacy against both (WCH-SK2) and its associated SCV form (0.67 and 0.76 log colony forming unit (CFU) reduction, respectively), which was attributed to ROS generated from the NIR activated β-NaYF:Yb/Tm@ZnO nanoparticles.