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.　©　2025　John　Wiley　&　Sons　Ltd.