Abstract Background Recent studies have shown that nurses have been more affected by the COVID-19 pandemic than any other group of hospital workers in terms of anxiety, depression, and burnout. Several clinical studies had previously demonstrated the effectiveness of mindfulness and compassion interventions in reducing burnout and emotional distress amongst healthcare professionals. Methods and analysis A parallel-group randomized controlled trial will assess the feasibility, acceptability, and efficacy of a mindfulness and compassion-focused programme on frontline nurses who had been working during the COVID-19 pandemic. Seventy-two participants will be recruited from Verona University Hospital Trust (Veneto Region, north-east Italy) and will be divided equally into an intervention group and a control group. Primary outcome will be assessed using the Emotional Exhaustion subscale of the Maslach Burnout Inventory General Survey (MBI-GS). Secondary outcomes will be measured by the Cynicism and Professional Efficacy subscales of the MBI-GS, the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder (GAD-7), the Insomnia Severity Index (ISI), the Impact of Stressful Events (IES-R), the Perceived Stress Scale (PSS), the Five Facet Mindfulness Questionnaire (FFMQ), and the Forms of Self-Criticising/attacking and Self-Reassuring Scale (FSCRS). Discussion The study aims to fill a gap in the literature and present a scientifically validated intervention for those healthcare professionals most exposed to the stressful conditions of working during the COVID-19 pandemic. Trial registration ClinicalTrials.gov; Identifier: NCT05308537