This study investigates a novel approach toward enhancing the efficacy of Lutetium-177 (Lu-177) radiopharmaceutical therapy by combining it with gold nanoparticles (AuNPs) in the HepG2 hepatic cancer cell line. Lu-177, known for its effective β radiation, also emits gamma rays at energies (113 keV and 208 keV) near the photoelectric absorption range, suggesting potential for targeted and localized radiation enhancement when used in conjunction with AuNPs. Thus, HepG2 cells were treated at two different activity levels (74 MBq and 148 MBq), with Lu-177 alone, with a combination of Lu-177 and AuNPs in two sizes (10 nm and 50 nm), while some received no treatment. Treatment efficacy was assessed by quantifying the radiation enhancement ratio (RER) and the apoptosis levels. The results reveal that combining Lu-177 with AuNPs significantly increases cell death and apoptosis compared to Lu-177 alone, with 10 nm AuNPs demonstrating superior effectiveness. Additionally, varying Lu-177 activity levels influenced the treatment outcomes, with higher activity levels further augmenting the therapeutic impact of combined therapy. These findings underscore the potential of utilizing Lu-177’s beta, but also gamma, emissions, traditionally considered non-therapeutic, for localized radiation enhancement when combined with AuNPs. This novel strategy leverages Lu-177 as an internal irradiator to exploit gamma radiation for a targeted therapeutic advantage without requiring nanoparticle functionalization. The study provides a promising approach to improving radionuclide therapy and sets the stage for future research aimed at optimizing cancer treatments through the combined use of Lu-177 and AuNPs.