Calcium is an essential macro element for growth of plants and algae; it regulates an impressive and diverse number of physiological processes. Research on the impact of calcium oxide nanoparticles (CaO NPs) is very little in the literature. In this work, responses of growth, photosynthesis, and antioxidant enzymes activities in Chlorella sp to short term treatment (5 hours) and to long-term treatment (5 days) by CaO NPs (0, 20, 40, 60, 80 and 100 ppm) were investigated. The results revealed that, the highest Chlorella sp growth and Chlorophyll content were recorded at 100 ppm CaO NPs. The highest photosynthetic oxygen evolution (PN) was recorded in the Chlorella cultures treated with 100 ppm CaO NPs during both long- and short-term experiments. Protein content was enhanced by treatment with CaO NPs up to 60 ppm CaO NPs. Catalase and guaiacol peroxidase activities recorded their highest values at 80 ppm CaO NPs. Total antioxidants increased in all CaO NPs treatments. In general, overall results of this research indicated that, treatment by CaO NPs improves growth, photosynthesis and modulates antioxidant responses of Chlorella sp. by stimulating antioxidation system.