Background and Aims <p>Arsenic contamination of paddy soils threatens rice productivity and food safety. This study evaluated the protective role of selenium against arsenic toxicity in four rice genotypes: a conventional line (F531B), a selenium-biofortified line (F531B-Se), and two naturally selenium-rich genotypes (Z2195B and Z2195A/YNS).</p> Methods <p>Plants were grown in soil amended with arsenic at 0–40&#xa0;mg&#xa0;kg⁻¹. Agronomic traits and yield components were measured, arsenic accumulation was quantified in roots, stems, leaves, and grains, and antioxidant enzyme activities (SOD, CAT, POD, and GR) were assessed at heading and maturity. Expression of key arsenic transport and detoxification genes was analyzed by targeted qPCR in roots, stems, and leaves at 30&#xa0;mg&#xa0;kg⁻¹ arsenic.</p> Results <p>Arsenic stress reduced growth and yield in a dose-dependent manner, with strong genotype-specific responses. The naturally selenium-rich genotype Z2195A/YNS showed the highest resilience, maintaining yield and accumulating the least arsenic in grains. Selenium enrichment enhanced antioxidant capacity across tissues, showing a biphasic response with peak activity under moderate arsenic stress. Compared with F531B, both naturally selenium-rich genotypes and the selenium-biofortified line maintained stronger redox balance. Gene expression analysis revealed reduced expression of arsenite influx transporters (<i>OsLsi1</i>, <i>OsLsi2</i>), enhanced vacuolar sequestration (<i>OsABCC1</i>), and activation of arsenate reduction and redox-related pathways.</p> Conclusions <p>Selenium accumulation or biofortification confers multi-level protection against arsenic toxicity by limiting arsenic translocation, strengthening antioxidant defenses, and reducing yield penalties. Z2195A/YNS represents a promising genotype for cultivation in arsenic-contaminated regions to improve rice productivity and food safety.</p>