Catalytic cross-coupling reactions, such as the Mizoroki-Heck reaction, play a crucial role in synthetic chemistry but pose significant environmental and health risks due to the toxicity of reaction components and their mixtures. In this study, we conducted a comprehensive cytotoxicity assessment of individual substances and complex reaction mixtures at different stages of the Mizoroki-Heck reaction. We demonstrate that the cytotoxicity of these mixtures often deviates from predictions on the basis of individual components due to synergistic and antagonistic interactions, with chlorobenzene-containing mixtures mostly exhibiting the lowest toxicity. Furthermore, our findings suggest that noncovalent interactions, including halogen bonding and π-stacking, significantly influence cytotoxicity. Notably, incomplete conversion of the reactants leads to an increase in mixture toxicity, emphasizing the importance of optimizing the reaction conditions. This study underscores the necessity of revising current chemical safety assessment strategies to account for complex molecular interactions in catalytic reactions.