<p>Isocycloseram is a next-generation isoxazoline insecticide for cucurbits, yet residue behavior in fresh cucumbers—often eaten raw—remains insufficiently characterized, including the role of its primary metabolite SYN 548569. We investigated dissipation under single (200 or 300 mg L⁻¹) and repeated applications (7-day interval), and quantified residues by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS); kinetic analysis yielded half-life (t½) and pre-harvest interval (PHI) estimates. A single spray deposited 0.09–0.10 mg kg⁻¹ on unpeeled fruit; residues declined with second-order kinetics (t½ = 0.74–0.99 day), reaching 0.01 mg kg⁻¹ in 6.7–8.3 days. Peeling removed ≈85% of surface deposits; despite slower internal dissipation (t½ ≈ 5.1 days), peeled fruit met the threshold within 1.6–3.1 day. A second application reduced initial deposits but markedly extended persistence on unpeeled cucumbers (t½ = 3.0–3.6 d; PHI = 17.5–19.0 days), whereas peeled samples still cleared the limit in &lt; 4 days. For SYN 548569 (assessed at 200 mg L⁻¹), peeled cucumbers showed higher initial levels yet a shorter t½ (0.71 day) than unpeeled (3.93 days). Overall, post-harvest peeling provides effective mitigation, while repeated high-dose sprays necessitate longer pre-harvest intervals (PHIs) for unpeeled produce to ensure consumer safety.</p> Graphical Abstract <p></p>