Background/Objectives: Naegleria fowleri is an opportunistic pathogen causing primary amoebic meningoencephalitis (PAM), a fatal neuroinflammatory disease with a high mortality rate of over 97%, in humans. Currently, there are no approved therapeutics for PAM, underscoring the urgent necessity of developing effective and safe drugs. This study aimed to evaluate the potential of ginsenosides Rb3 and Rc as alternative or supplementary drug candidates for PAM by assessing their anti-amoebic activities against N. fowleri. Methods: Anti-N. fowleri activities of ginsenosides Rb3 and Rc and their cytotoxicity to C6 glial cells were evaluated by cell viability assay. The underlying anti-amoebic mode of action of Rb3 and Rc was analyzed by a series of assays for apoptosis–necrosis, TUNEL, intracellular reactive oxygen species (ROS), mitochondrial dysfunction, ATP production, caspase-3, and autophagy. The expression profiles of apoptosis- and autophagy-related genes were also analyzed. Results: Rb3 and Rc effectively induced death of N. fowleri trophozoites with IC50 values of 94.71 ± 1.63 μM and 126.99 ± 1.88 μM, respectively. However, Rb3 and Rc showed no significant cytotoxicities against C6 glial cells, suggesting their selective anti-N. fowleri activities. Typical apoptosis signals, such as apopxin staining and DNA fragmentation, were detected in amoebae upon treatment with Rb3 or Rc. These two ginsenosides enhanced ROS production and induced mitochondrial dysfunction in the amoebae. Enhanced caspase-3 activity and autophagy formation were also identified in amoebae treated with Rb3 or Rc. Conclusions: These results provide the first evidence that ginsenosides Rb3 and Rc induce apoptosis-like programmed cell death in N. fowleri, suggesting that they are potential candidates in developing novel therapeutic strategies against PAM.