Phytoremediation is a low-cost, sustainable option to remediate polluted soils; however, synergistic or antagonistic effects of mixed contaminants, especially co-existing multiple organic and heavy metal contaminants, are not systematically explored. In the current study, a laboratory investigation is conducted to assess the interactive effects of organic and heavy metal contaminants when they are present in the soil separately and in combination. A silty clay soil was contaminated with: (1) naphthalene and phenanthrene (representative organic contaminants), (2) lead (Pb), cadmium (Cd), and chromium (Cr) (representative heavy metals), and (3) a combination of these organic and heavy metal contaminants. Four different plant species, specifically Avena sativa (oat plant), Lolium perenne (perennial rye grass), Festuca arundinacea (tall fescue), and Helianthus annuus (sunflower), were selected. Results showed that the growth of plants was similar in both uncontaminated soil and the soil with organic contaminants. However, the plants underwent maximum level of distress in the heavy metal contaminated soil, with Cr being more phytotoxic than all other heavy metal combinations studied. Sunflower did not germinate, while germinated oat plants did not survive when Cr alone was present. Co-existence of Cr with other metals caused less phytotoxicity, whereas Pb did not exhibit any significant phytotoxicity when Cd and Cr co-existed in the soil. The plants in the mixed organic and heavy metal contaminated soil performed better than those plants in soils with heavy metal contaminants. Complete degradation of naphthalene and significant reduction in the concentration of phenanthrene were found in all the experiments, including the unplanted pots. However, the presence of organic contamination inhibited the extraction of heavy metals from the soil by the plants. Oat plant and sunflower could reduce Pb and Cd concentrations both in soils solely contaminated with one of these metals and in mixed metal contaminated soils. Phytoextraction of Cd was inhibited in the presence of other metals. Overall, the effectiveness of phytoremediation and the potential synergistic or antagonistic effects of different contamination scenarios were found to be influenced by several factors. These factors include the specific type of contaminants, the choice of plant species, and whether the contamination was mixed or individual in nature.