The increasing reuse of treated wastewater (WW) for irrigation brings with it a need to reconsider irrigation water quality criteria because of the expected lower quality of WW. In particular, the impacts of higher sodium and dissolved organic carbon (DOC) concentrations on soil permeability must be evaluated in practical field settings over long periods of WW reuse. Here we report the long-term impact of WW reuse for irrigation on soils at three different semiarid-zone field sites under row crop or orchard agriculture. The soils contain about 60% clay, dominated by smectite, and present an order of magnitude variation in calcite content (1–11%). In two of the sites, parcels irrigated with freshwater (FW) are available for comparison. Our results show an increasing sodicity hazard and a decreasing saturated soil hydraulic conductivity (Ks) from WW irrigation, although the depth profiles of soil chemical and physical properties were highly site-specific. Despite this spatial variability, all of the data on sodicity hazard, represented by the relationship between exchangeable sodium percentage (ESP) and the soil sodium adsorption ratio (SAR), could be incorporated into a single Gapon constant for calcium–sodium exchange whose values depended uniformly on the ratio of soil DOC concentration to calcite content. Moreover, all of the data on Ks, for both FW and WW irrigation, could be incorporated into a single power-law relationship involving the ratio of ESP to soil DOC. These two relationships unify complex interactions between sodicity and organic matter (OM) that influence soil permeability to yield simple correlations with predictive power. The main detrimental effect of WW application was related to sodicity hazard. Therefore, effort should be invested in reducing the SAR of WW for irrigation. This could be achieved, for example, by mixing WW with FW, including desalinized water, when and if available.