In our research, an emerging magnetic covalent organic framework (FeO@SiO-BD-DADB-COF) was formulated through Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), Several parameters affecting the extraction process were refined. Accordingly, a novel method of determining 15 macrolides (MALs) in honey and water was established through the FeO@SiO-BD-DADB-COF as a magnetic solid-phase extraction (MSPE) adsorbent and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). In consequence, the standard curves for the 15 MALs exhibited an exceptional linearity from 0.1 to 200 μg L, and the correlation coefficients ( ) varied from 0.9990 to 0.9999. The recoveries fell between 70.01% and 115.56%, with the relative standard deviations (RSDs) being below 9.93% ( = 5). The detection limits reached 0.001-0.075 μg L with the quantification limits being 0.004-0.228 μg L. Ultimately, the method was excellently applied to the analysis of MALs in honey and water.