Colorectal cancer (CRC) is the third most common malignancy and the second most lethal cancer worldwide and has become a significant burden on global healthcare. The primary treatments for CRC include surgery, chemotherapy, and targeted therapy. However, these approaches face several limitations, such as invasive administration, poor patient compliance, systemic toxicity, drug resistance, and recurrence. Thus, alternative therapeutic strategies to overcome these challenges are urgently needed. Oral administration represents a promising approach for CRC treatment because of its noninvasive nature, safety, ease of self-administration, and high patient compliance. Moreover, when applied in CRC treatment, oral therapies can potentially increase therapeutic efficacy and reduce systemic toxicity via local treatment. Furthermore, the unique pathophysiological features of CRC, such as the overexpression of certain receptors and dysbiosis, present valuable opportunities for the development of advanced oral therapies. This review focuses on cutting-edge oral therapies for CRC, including nanomedicine-based and bacteria-modulating strategies. These approaches show significant promise for improving therapeutic outcomes and can be combined with existing treatment modalities to improve efficacy and minimize adverse effects. Additionally, we provide critical perspectives on the challenges and future perspectives of these strategies for CRC management. This review aims to provide novel insights into the design and advancement of oral therapies, paving the way for more effective and patient-friendly CRC treatments.Copyright © 2025. Published by Elsevier B.V.