Colorectal cancer is the second leading cause of cancer-related deaths worldwide. CRC is often treated with intravenous 5-fluorouracil (5FU). However, 5FU frequently shows low therapeutic efficacy and serious adverse events. Particulate drug carriers able to enhance intracellular delivery could be advantageous, since higher 5FU concentrations would be engulfed by cancer cells during a relatively short residence within the rectal space to improve local anti-cancer efficacy. Therefore, we propose a novel material based on a zirconium-based metal-organic framework (MOF), PCN-223, as a potential carrier of 5FU for rectal delivery of treatment for CRC. PCN-223 nanoparticles, prepared by the solvothermal method, exhibited a highly porous structure, whereby 79.4 μg/mg 5FU could be encapsulated and released in a sustained manner over 2 h in vitro. PCN-223 was internalized by the human colorectal cancer cell line, HCT-116, within 2 h, representing the period that rectally delivered particles reside within the rectum. Consequently, 5FU-loaded PCN-223 (5FU@PCN-223) treatment decreased the viability of HCT-116 cells compared with treatment with a bolus 5FU solution, suggesting improved drug efficacy over a short exposure time. Therefore, PCN-223 may be a promising carrier for rectal delivery of 5FU for treatment of colorectal cancer.