Background <p>Oncology nurses face long-term emotional pressures that contribute to compassion fatigue, decreased resilience, and a lack of social support. The number of interventions integrated into clinic workflows or directed by nursing management is modest. This study examined a mindfulness-based resilience intervention offered by nursing leadership.</p> Methods <p>In a single-blind, parallel-group randomised controlled trial done in a single hospital, 100 oncology nurses were randomly allocated (1:1) to either mindfulness-based intervention (eight weeks) or standard institutional training. Randomisation was conducted using a computer-generated allocation sequence. Because of the intervention nature, group assignment was known to the participants, yet outcome assessors and data analysts were not allocated. The mindfulness-based programme in the intervention group commenced immediately after the baseline assessment, whereas the institutional training in the control group was undertaken during the same period. Compassion fatigue, resilience, and perceived social support were the primary outcomes, measured at baseline and at weeks 1, 3, 8, and 12. Serum cortisol levels and indicators provided by smartwatches were used to assess physiological stress. Pathways of biomarkers were analysed through mediation analysis. All analyses were carried out on an intention-to-treat basis.</p> Findings <p>The management-led mindfulness programme resulted in a significant decrease in compassion fatigue markers, enhanced resilience, and increased perceived social support among participating nurses. General Linear Model repeated-measures analysis revealed significant time × group effects across psychological and physiological outcomes (Pillai’s Trace = 0.95–0.99, <i>p</i> &lt; 0.001), with marked reductions in serum cortisol and smartwatch-derived stress. Cortisol partially mediated the association between social support and psychological outcomes (indirect effect = 0.12, 95% CI 0.03–0.22), and structural equation modelling confirmed this pathway with excellent fit indices (CFI = 0.998; RMSEA = 0.034). The programme was well tolerated, with no adverse events reported.</p> Results <p>Oncology nurses’ psychological and physiological well-being improves with a management-led mindfulness intervention. Resilience training integrated into nursing leadership is a viable solution to the high-stress conditions in clinical settings. It should be adopted more generally and evaluated in the future.</p> Clinical trial number <p>Not applicable.</p>