The aim of the present study was to improve the estimation of soil-derived uranium absorption in humans. For this purpose, an in vitro solubility assay was combined with a human study by using a specific edible soil low in uranium. The mean bioaccessibility of the soil-derived uranium, determined by the solubility assay in artificial gastrointestinal fluid, was found to be 7.7% with a standard deviation of 0.2%. The corresponding bioavailability of the soil-derived uranium in humans was assumed to be log-normal distributed with a geometric mean of 0.04% and a 95% confidence interval ranging from 0.0049% to 0.34%. Both results were used to calculate a factor, denoted as fA(sol), which describes the relation between the bioaccessibility and the bioavailability of soil-derived uranium. The geometric mean of fA(sol) was determined to be 0.53% with a 95% confidence interval ranging from 0.06% to 4.43%. Based on fA(sol), it is possible to estimate more realistic values on the bioavailability of uranium for highly uranium-contaminated soils in humans by just performing the applied solubility assay. The results of this study can be further used to obtain more reliable results on the internal dose assessment of ingested highly uranium-contaminated soils.