Nanoporous metal-organic frameworks (MOFs)have been gaining a reputation for their drug delivery applications.In the current work, MOF-801 was successfully prepared by afacile, cost-efficient, and environmentally friendly approachthrough the reaction of ZrCl4and fumaric acid as organic linkersto deliver 5-fluorouracil (5-FU). The prepared nanostructure wasfully characterized by a series of analytical techniques includingFourier transform infrared spectroscopy, powder X-ray diffraction,field-emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, UV-vis spectroscopy,1H NMR spectroscopy,thermogravimetric analysis, high-performance liquid chromatog-raphy, and Brunauer-Emmett-Teller analysis. MOF-801 could beused for the delivery of the anticancer drug 5-FU due to its highsurface area, suitable pore size, and biocompatible ingredients. Based on in vitro loading and release studies, a high 5-FU loadingcapacity and pH-dependent drug release behavior were observed. Moreover, the interactions between the structure of MOFs and 5-FU were investigated through Monte Carlo simulation calculations. An in vitro cytotoxicity test was done, and the results indicatedthat 5-FU@MOF-801 was more potent than 5-FU on SW480 cancerous cells, indicating the highlighted role of this drug deliverysystem. Finally, the kinetics of drug release was investigated.