RATIONAL: Benzophenone derivatives, commonly used as UV filters in personal care products (PCPs), are widely prevalent and raise concerns due to their endocrine-disrupting effects. Sensitive and efficient analytical methods are in demand for their detection. In this study, we developed a TAPB-DMTP-covalent organic framework (COF) nanofilm-assisted laser desorption ionization mass spectrometry (LDI-MS) method for the quantitative analysis of 2,4-dihydroxybenzophenone (BP-1) in PCPs. METHODS: The TAPB-DMTP-COF nanofilm was synthesized on indium tin oxide (ITO) glass and utilized as an LDI-MS substrate. The performance of TAPB-DMTP-COF nanofilm-assisted LDI-MS for analyzing small molecules (e.g., benzophenone derivatives, phthalates, amino acids, sugars, and nucleosides) was compared to conventional organic matrices (α-cyano-4-hydroxycinnamic acid [CHCA], 2,5-dihydroxybenzoic acid [DHB], and sinapinic acid [SA]). The reproducibility, salt resistance, sensitivity, and stability of the method were further evaluated. Finally, the technique was applied to quantify BP-1 in PCPs. RESULTS: The TAPB-DMTP-COF nanofilm-assisted LDI-MS provided stronger mass spectral signals and cleaner backgrounds for small molecules compared to CHCA, DHB, and SA. The method exhibited high reproducibility (RSD = 6.10%) and stability for up to 30 days. BP-1 in PCPs was quantified with excellent linearity (1-20 μg/mL, r = 0.9993), a low detection limit (0.3 μg/mL), and recovery rates of 94.2%-104.4%, demonstrating the potential of TAPB-DMTP-COF nanofilm for sensitive and reliable small-molecule analysis. CONCLUSION: TAPB-DMTP-COF nanofilm-assisted LDI-MS offered the advantages of rapid analysis, clean backgrounds, and reproducibility for detecting small molecules, including benzophenone derivatives. This method successfully quantified BP-1 in PCPs, highlighting its suitability for analyzing complex samples.