Burnout syndrome (BS) has been classified as an independent ‘work-related phenomenon’, however, there is still an important discussion on whether BS is a unique clinical construct due to the overlapping symptoms with other domains of negative affect such as symptoms of depression, anxiety, and irritability. Thus, we investigated the common and dissociable aspects between BS and domains of negative affect such as depression, anxiety, and irritability through a cross-sectional study with 3428 essential service professionals from a national project during the COVID-19 pandemic. Participants were assessed with Burnout Assessment Tool (BAT) and the Patient-Reported Outcomes Measurement Information System (PROMIS) scales to assess the severity of depression, anxiety, and irritability. The discriminability between the constructs was investigated using correlation tests, Bifactor Exploratory Structural Equation Modeling Bifactor (ESEM), and network analyzes. The mean correlation among the four subscales of BAT-12 was stronger with each other than with depression, anxiety, and irritability. Both ESEM and network analysis, despite showing shared characteristics, clearly delineated that Burnout domains were dissociable from other domains of negative affect. Our findings corroborate the ICD-11 strategy to include BS as a separate entity that cannot be fully explained by variance accounted for by other domains.