As the second most common cause of death globally, tumor significantly impacts human health and quality of life. Although monotherapy has achieved remarkable progress, its therapeutic effectiveness remains less than ideal. The current strategy is increasingly inclined towards a combination of different treatments. Combination therapy is conducive to rectifying the inherent flaws of monotherapy, surmounting multi-drug resistance, and attaining a synergistic effect. The advancement of nanotechnology offers an unparalleled opportunity for anti-tumor combination therapy. Metal-organic frameworks (MOFs) possess distinctive structural features, including adjustable pore sizes, diverse organic ligands and metal ion centers, as well as the modifiability of functional sites. These characteristics render the combined application of multiple therapeutic approaches feasible. This article provides a review of the research on MOFs-based nano drug delivery platform for anti-tumor combination therapy under physiological conditions or exogenous stimulation. The opportunities and challenges of MOFs entering the clinic for anti-tumor combination therapy are also discussed to provide reference for the further application of MOFs, and provide a novel idea for the research of MOFs-based drug delivery system.