Voriconazole is a triazole broad-spectrum antifungal medication often used to treat fungal infections caused by Aspergillus and Fusarium species. One of the main challenges associated with the implementation of this medication is its narrow therapeutic concentration range, demonstrating toxicity at concentrations above 6 μg/mL and limited efficacy at concentrations below 2 μg/mL. As a result, methodologies which permit the rapid and accurate quantitation of voriconazole in patients are highly desirable. In this work two different approaches based on coated blade spray directly coupled to mass spectrometry (CBS-MS) are introduced; each enabling the quantitation of voriconazole in plasma samples with a simple and fast sample preparation and no chromatographic step. The first approach involves a rapid extraction (1 min) of the target analyte from 300 μL of human plasma using conventional laboratory vessels (e.g. vial, 96-well plate). Alternatively, the second strategy consists of a 2 min extraction from a plasma droplet (10 μL) placed on the coated area of the blade. Both procedures were successfully validated and good linearity (R2 ≥ 0.998), accuracy (91–122%) and precision (<8%) were attained in the concentration range evaluated (0.1–50 μg/mL). Moreover, very good results in terms of relative matrix effects were obtained given that the slopes of the calibration curves constructed in five different plasma lots exhibited relative standard deviation (RSD) values below 7%. Herein we demonstrated that CBS-MS is a technology suitable for the ultra-fast determination of voriconazole in human plasma samples. Indeed, the proposed methodology can be easily used either for routine drug monitoring or for in vitro pharmacokinetic studies in applications where very small sample volumes are available and great temporal resolution is needed.