A combination of targeted and untargeted approaches for a single-injection LC-HRMS exposomics/metabolomics is described. The method is the first of its kind to make use of the Zeno trap in MRM-HR mode, recently developed with the aim to correct for duty cycle issues related to TOF instruments, allowing for increased sensitivity. The results highlight the method's capabilities and its potential to detect xenobiotics present at low concentrations that otherwise would not be detected (or would be poorly detected) using a SWATH-only methodology. The method also allows for future customized developments, not only in terms of which compounds to include in the targeted list, but also regarding the choice of a semi or absolute quantitation. In the field of metabolomics, for instance, this approach could be employed to detect poorly ionized and/or low concentration compounds, e.g., endogenous hormones. Additionally, in applications in which a limited amount of sample is available (such as for serum samples for premature infants) or sample amount is limited by the sample collection technique (such as dried blood spots or volumetric microsampling devices) may also benefit, producing targeted and untargeted data acquisition in a single injection. In conclusion, we demonstrated that this type of data acquisition shows great potential for future application in any field of small molecules "omics" and can be an interesting alternative for the long-time discussed compromise between sensitivity and coverage.