Rice is an important food crop that is susceptible to arsenic (As) contamination under paddy soil conditions depending on As uptake characteristics of the rice genotypes. Here we unveiled the significance of eighteen (fine and coarse) rice genotypes against As accumulation/tolerance, morphological and physiological response, and antioxidant enzymes-enabled defense pathways. Arsenic significantly affected rice plant morphological and physiological attributes, with relatively more impacts on fine compared to coarse genotypes. Grain, shoot, and root As uptake were lower in fine genotypes (0.002, 0.020, and 0.032 mg pot−1 DW, respectively) than that of coarse (0.031, 0.60, and 1.2 mg pot−1 DW, respectively). Various biochemical (pigment contents, hydrogen peroxide, lipid peroxidation) and defense (antioxidant enzymes) plant parameters indicated that the fine genotypes, notably Kainat and Basmati-385, possessed the highest As tolerance. Arsenic-induced risk indices exhibited greater hazard quotient (up to 1.47) and carcinogenic risk (up to 0.0066) for coarse genotypes compared to the fine ones, with the greatest risk for KSK-282. This study elaborates the pivotal role of genotypic variation among rice plants in As accumulation, which is crucial for mitigating the associated human health risk. Further research is required on molecular aspects, e.g., genetic sequencing, to examine rice genotypes variation in defense mechanisms to As contamination.