Environmental risk assessment of sites contaminated with chemicals needs to also consider mixtures of chemicals as these toxicants act more differently in a mixture than when they occur alone. In this study, we describe, for the first time, the use of a full factorial design experiment to evaluate the toxicity of a quaternary mixture comprising two polycyclic aromatic hydrocarbons (PAHs; benzo[a]pyrene (BaP) and phenanthrene (Phe)) and two heavy metals (cadmium (Cd) and lead (Pb)) toward a soil microalga, Chlorococcum sp. MM11. Biomass, in terms of cell number, and proline accumulation were used to evaluate toxicity responses. Factorial analysis of the data revealed statistically significant interaction effects between the mixtures of toxicants on 96-h biomass endpoint, while no significant interaction effects were observed on proline accumulation in the microalga. A comparison of the data on the toxicity of individual chemicals and those of the factorial main effect analysis clearly showed that Cd is more toxic to the alga, followed by BaP, Pb, and Phe. There was a substantial heavy metal accumulation and PAH degradation by the strain MM11 at EC10 and EC50 of the chemical mixtures.