BACKGROUND: Novel virus outbreaks, such as the COVID-19 pandemic, may increase psychological distress among frontline workers. Psychological distress may lead to reduced performance, reduced employability or even burnout. In the present study, we assessed experienced psychological distress during the COVID-19 pandemic from a self-determination theory perspective. METHODS: This mixed-methods study, with repeated measures, used surveys (quantitative data) combined with audio diaries (qualitative data) to assess work-related COVID-19 experiences, psychological need satisfaction and frustration, and psychological distress over time. Forty-six participants (nurses, junior doctors, and consultants) completed 259 surveys and shared 60 audio diaries. Surveys and audio diaries were analysed separately. RESULTS: Quantitative results indicated that perceived psychological distress during COVID-19 was higher than pre-COVID-19 and fluctuated over time. Need frustration, specifically autonomy and competence, was positively associated with psychological distress, while need satisfaction, especially relatedness, was negatively associated with psychological distress. In the qualitative, thematic analysis, we observed that especially organisational logistics (rostering, work-life balance, and internal communication) frustrated autonomy, and unfamiliarity with COVID-19 frustrated competence. Despite many need frustrating experiences, a strong connection with colleagues and patients were important sources of relatedness support (i.e. need satisfaction) that seemed to mitigate psychological distress. CONCLUSION: The COVID-19 pandemic resulted in an increase of psychological distress among frontline workers. Both need frustration and need satisfaction explained unique variance of psychological distress, but seemed to originate from different sources. Challenging times require healthcare organisations to better support their professionals by tailored formal and informal support. We propose to address both indirect (e.g. organisation) and direct (e.g. colleagues) elements of the clinical and social environment in order to reduce need frustration and enhance need satisfaction.