Oxo-anions and cations of heavy metals often exist together in the environment. As they have opposite charges, it is a major challenge to remove them simultaneously and efficiently. In this work, a novel 2D mesoporous guanidinium-based ionic covalent organic framework (iCOF), exhibiting excellent reductivity and stability for the removal of oxo-anions (Cr(VI), V(V), Se(IV)), and cations (Pb(II)) in the pH range of 3–6, was used. In a single medium, rapid removal occurred within one hour with maximum removal capacities of 607.2, 589.6, and 221.6 mg g^-1 for Cr(VI), V(V), and Se(IV), respectively, at 30 ˚C. In addition, the coexistence of Pb(II) with Cr(VI)/V(V)/Se(IV) in the binary medium significantly increased the removal efficiency of both cations and oxo-anions using the iCOF composite. Based on the kinetic and isothermal mathematical models that reveal the chemical nature of adsorption throughout the process. Inspiringly, the system was tested in four types of wastewaters with different pH values to show its practical applicability. The results show that 1 kg of iCOF can decontaminate more than 2000 litres of ⁓10 mg L^-1 Cr(VI), V(V), and Se(IV), at a cost of USD 579 to the EPA’s effluent discharge limit. In addition, the comprehensive work carried out for this study has broader applications that can be used to treat toxic cationic and oxo-anionic heavy metal contaminants from a wide variety of wastewaters.