We have highlighted that exposure of base-metal dental casting alloys to the acidogenic bacterium Streptococcus mutans significantly increases cellular toxicity following exposure to immortalized human TR146 oral keratinocytes. With Inductively Coupled Plasma-Mass Spectrometry (ICP-MS), S. mutans-treated nickel-based (Ni-based) and cobalt-chromium-based (Co-Cr-based) dental casting alloys were shown to leach elevated levels of metal ions compared with untreated dental casting alloys. We targeted several biological parameters: cell morphology, viable cell counts, cell metabolic activity, cell toxicity, and inflammatory cytokine expression. S. mutans-treated dental casting alloys disrupted cell morphology, elicited significantly decreased viable cell counts (p < 0.0001) and cell metabolic activity (p < 0.0001), and significantly increased cell toxicity (p < 0.0001) and inflammatory cytokine expression (p < 0.0001). S. mutans-treated Ni-based dental casting alloys induced elevated levels of cellular toxicity compared with S. mutans-treated Co-Cr-based dental casting alloys. While our findings indicated that the exacerbated release of metal ions from S. mutans-treated base-metal dental casting alloys was the likely result of the pH reduction during S. mutans growth, the exact nature of mechanisms leading to accelerated dissolution of alloy-discs is not yet fully understood. Given the predominance of S. mutans oral carriage and the exacerbated cytotoxicity observed in TR146 cells following exposure to S. mutans-treated base-metal dental casting alloys, the implications for the long-term stability of base-metal dental restorations in the oral cavity are a cause for concern.