Combination therapy has long been applied to enhance therapeutic effect and deal with the occurrence of multi-drug resistance in cancer treatment. However, the overlapping toxicity of multiple anticancer drugs to healthy tissues and increasing financial burden on patients emerged as major concerns. As promising alternatives to chemo agents, repurposed non-chemo drugs and dietary phytochemicals have been investigated as adjuvants to conventional anti-tumor therapeutics, offering a safe and economic strategy for combination therapy. In this review, we aim to highlight the advances in research about combination therapy using conventional therapeutics and repurposed drugs or phytochemicals for an enhanced anti-tumor efficacy, along with the mechanisms involved in the synergism. Beyond these, we outlined the potential challenges and solutions for clinical translation of the proposed combination therapy, providing a safe and affordable strategy to improve the reach of cancer therapy to low income regions with such new tricks of old drugs.