Iron (Fe) plays a pivotal role in biogeochemical cycling in the soil-plant-human continuum; however, much research has focused on Fe deficiency with limited knowledge about Fe toxicity impacts on micronutrient (e.g., zinc: Zn) accumulation in cassava, an important staple tuber food in the Tropics. A sand-hydroponic-hybrid technique was undertaken for 60 days to investigate the effects of variable Fe concentrations (0.1–500 μmol Fe L−1) on the root-proton and root-organic acid release, rhizosphere Fe solubility, and levels of cassava nutrient accumulation. The results showed that high Fe concentrations (50–500 μmol Fe L−1) significantly decreased the root (0.34–0.51 g dry weight) biomass compared to the control (0.82–0.83 g dry weight). The Fe concentrations significantly regulated the net proton release from the roots by upregulating (25–45 μmol L−1 h−1 g−1 fresh weight root) and downregulating (1.8–7.1 μmol L−1 h−1 g−1 fresh weight root) the net proton efflux at low (1.0 μmol Fe L−1) and high Fe concentrations (500 μmol Fe L−1), respectively. Succinic acid was the sole organic acid observed and only in the Fe-sensitive cultivar. The water-extractable Fe in the rhizosphere sand (average 3.37 mg kg−1) was lower than in the bulk sand (average 5.31 mg kg−1), indicating that net proton efflux controlled rhizosphere Fe solubility. The high Fe concentrations significantly decreased Zn accumulation (20–29 mg Zn kg−1) but increased phosphorus (P) accumulation (2.7–3.4 g P kg−1) in the roots compared to the control (48–59 mg Zn kg−1 and 2.0–2.3 g P kg−1, respectively), implying that Fe toxicity could be responsible for the undernourished Zn content in the tuber. This study suggested the importance of alleviating Fe toxicity in soil-plant systems to mitigate cassava root Zn deficiency, which is relevant to human Zn malnutrition in countries consuming cassava as the main staple diet.