Introduction: Effect of water stress on the physiology and biochemistry of two different Coleus species, Coleus forskholii and Coleus amboinicus, was studied. Materials and methods: Drought stress was imposed by withholding the water supply until leaf water potentials reached -0.4, -0.8, and -1.2 MPa. Physiological parameters such as relative water content and water uptake capacity were studied along with lipid peroxidation, superoxide, H2O2, and (OH)-O-center dot accumulation-, 1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging assays. Antioxidant defense system in Coleus under drought stress was studied by quantifying the Trolox equivalent antioxidant capacity, ascorbic acid, reduced glutathione-, and alpha-tocopherol content as well as activities of superoxide dismutase, catalase, ascorbate peroxidase, peroxidase, and glutathione reductase. Accumulation of osmolytes proline, glycine betaine, and phytohormone abscisic acid was also used as key parameters for assessing their performance. Results: There was a marked variation in the antioxidative defense system and osmolyte accumulation in these two species under drought stress. Relative water content was reduced and water uptake capacity was increased. Discussion: A comparative study in the perspectives of osmolyte accumulation, antioxidant, and physiological responses inferred C. amboinicus as a drought stress-tolerant species when compared to C. forskholii.