The co-occurrence of cadmium (Cd) pollution and selenium (Se) deficiency commonly exists in global soils, especially in China. As a result, there is great interest in developing practical agronomic strategies to simultaneously achieve Cd remediation and Se mobilization in paddy soils, thereby enhancing food quality/safety. To this end, we conducted a field-plot trial on soils having high geological background levels of Cd (0.67 mg kg-1) and Se (0.50 mg kg-1). We explored 12 contrasting fertilizers (urea, potassium sulfate (K2SO4), calcium-magnesium-phosphate (CMP)), amendments (manure and biochar) and their combinations on Cd/Se bioavailability. Soil pH, total organic carbon (TOC), soil available Cd/Se, Cd/Se fractions and Cd/Se accumulation in different rice components were determined. No significant differences existed in mean grain yield among treatments. Results showed that application of urea and K2SO4 decreased soil pH, whereas the CMP fertilizer and biochar treatments increased soil pH. There were no significant changes in TOC concentrations. Three treatments (CMP, manure, biochar) significantly decreased soil available Cd, whereas no treatment affected soil available Se at the maturity stage. Four treatments (CMP, manure, biochar and manure+urea+CMP+K2SO4) achieved our dual goal of Cd reduction and Se enrichment in rice grain. Structural equation modeling (SEM) demonstrated that soil available Cd and root Cd were negatively affected by pH and organic matter (OM), whereas soil available Se was positively affected by pH. Moreover, redundancy analysis (RDA) showed strong positive correlations between soil available Cd, exchangeable Cd and reducible Cd with grain Cd concentration, as well as between pH and soil available Se with grain Se concentration. Further, there was a strong negative correlation between residual Cd/Se (non-available fraction) and grain Cd/Se concentrations. Overall, this study identified the primary factors affecting Cd/Se bioavailability, thereby providing new guidance for achieving safe production of Se-enriched rice through fertilizer/amendment management of Cd-enriched soils.