Toxic metal contamination of soil remains a critical global challenge due to the persistence, bioaccumulation, and irreversible toxicity of these metals. Cadmium (Cd), lead (Pb), mercury (Hg), arsenic (As), chromium (Cr) and nickel (Ni) are the most common toxic metals that threaten food security, ecosystem stability, and human health. While conventional physicochemical remediation technologies provide rapid pollutant removal, they are constrained by high economic costs, secondary pollution risks, and long-term soil degradation. Biological approaches, particularly phytoremediation and microbial mitigation, offer environmentally compatible alternatives; however, their field-scale performance is often limited by low biomass production, restricted metal bioavailability, microbial instability, and heterogeneous soil conditions. This review critically synthesizes recent advances that move beyond standalone biological strategies toward integrated, multi-scale remediation frameworks. We evaluate the mechanistic basis and performance of nano-assisted phytoremediation, biochar-mediated stabilization, omics-guided plant–microbe optimization, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein systems (CRISPR/Cas) for enhancing metal transport, chelator biosynthesis, antioxidant defense, and microbial detoxification pathways. Emerging evidence indicates that nano-enabled amendments and biochar composites can reduce bioavailable Cd fractions by up to 75%, while omics-driven microbial consortia and targeted genome editing improve tolerance and accumulation efficiency in key crops such as rice and sorghum. Importantly, we assess translational barriers including nanoparticle ecotoxicity, off-target genome effects, regulatory constraints, biomass disposal, and life-cycle sustainability that currently limit large-scale deployment. By integrating mechanistic insights with field validation data, risk assessment considerations, and technology readiness evaluation, this review proposes a conceptual roadmap for scalable, eco-efficient soil restoration. The convergence of nanotechnology, systems biology, microbiome engineering, and precision genome editing represents a transformative pathway for next-generation remediation strategies capable of restoring contaminated soil while safeguarding environmental and public health.