This study reports on a wide-scale, systematic sampling program over two consecutive years investigating As and Cd and associated implications for human health in farming areas of the dry zone, Sri Lanka, where chronic kidney disease with unknown etiology (CKDu) is endemic. Surface soil (0–15 cm), fertilizer and rice seed samples were collected in 2017 and 2018 from three CKDu affected areas [Medawachchiya (M), Padaviya (P) and Giradurukotte (G)], and a non-affected control site [Hambanthota (H)]. All inorganic fertilizer samples showed low As (< 30 mg kg−1) and Cd (< 1.25 mg kg−1) concentrations, less than European Union guideline values, and no correlation with soil concentrations. Arsenic (≤ 3.8 mg kg−1) and Cd (≤ 3.0 mg kg−1) in the 400 soil samples analyzed were low at all four locations, and soils were considered suitable for sensitive and agricultural use. A human health risk assessment demonstrated the As and Cd concentrations in surface soil provided no concern for non-carcinogenic risk, and negligible or acceptable carcinogenic risk for all locations sampled. The As and Cd in rice seeds harvested were also less than detection limits (< 0.1 mg kg−1). This work provides clarity around As and Cd baseline values in certain farm soils of the dry zone Sri Lanka, and no substantive evidence that the levels of As and Cd in the surface soils contribute to CKDu in local agricultural populations. Additional sampling of subsurface soil and water resources would satisfy some uncertainties with the risk assessment described.