Developing agents that can accurately differentiate tumors from normal healthy tissues is of utmost importance for safe cancer therapy. Active targeting has been considered as an effective technique for tumor recognition. In this work, we demonstrate a folate-functionalized nanoscale covalent organic framework (FATD nCOF) highly specific to cancer cells through active targeting of their enriched folate receptors (FRs). The FATD nCOF prepared by simple post-synthetic modification of the COF surface defeats disperses well in water and exhibits a high loading capacity for various anticancer drugs. The biocompatible FATD nCOF is selectively internalized by FR-harboring cancer cells and consequently augments the efficacy of the loaded drug, Withaferin A (Wi-A), for targeted cancer cell killing. In biomolecular mechanism studies, Wi-A-loaded FATD (FATD@Wi-A) nanocomposites show remarkably a higher rate of apoptosis in FR-enriched cancer cells. Comparative analyses of FR-positive and FR-negative tumor xenografts reveal enhanced selective antitumor activity of FATD@Wi-A nanotherapeutics. Taken together, the study findings suggest that FATD nCOF holds great promise for active targeting of tumors in vivo. Our simple yet effective technology might be valuable for creating new state-of-the-art COFs for chemical and biomedical applications.