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Sea cucumbers, belonging to the phylum Echinodermata, are known to possess valuable bioactive compounds that have medicinal properties. In several countries, such as Korea, China, and Japan, they are cultured in the aquaculture industries for food and medicinal purposes. Research has shown that different species of sea cucumbers each possesses unique medicinal values. As a result, we strive towards finding species with better health resilience in aquaculture system to be cultured for nutritional and medicinal purposes. In this paper, we compared the physiological and immunological parameters of three species of sea cucumbers, Cucumaria frondosa (C. frondosa), Isostychopus badionotus (I. badionotus), and Pentacta pygmaea (P. Pygmaea) from the waters of the eastern United States as they have not been studied extensively. Four different cells of sea cucumbers, phagocytic, red spherule, white spherule, and vibratile cells, that contribute to their immunity were counted. C. frondosa exhibited the highest concentrations of phagocytic cells, white spherule cells, and vibratile cells, compared to the two other species. Due to its high phagocytic cell concentration, the highest phagocytic capacity was seen in C. frondosa although it was not statistically significant. We also observed that C. frondosa had the highest total cell count and the highest concentration of coelomic protein among the three species. Lastly, C. frondosa possessed the highest lysozyme activity. Taken together, we concluded that C. frondosa is the best of the three species compared to be reared in the aquaculture systems for use in the food and biomedicine industries due to its immunological and physiological properties.