Aim. The aim was to explore the association between nursing professional values (NPV) and mental health among registered nurses (RN) in Spain. Background. Nursing is a profession rooted in strong professional values, which guide and shape clinical practice and occupational behaviors. NPV should serve as a source of support in situations of great uncertainty. Methods. A cross‐sectional study was conducted during the remission phase of the second wave of the COVID‐19 pandemic (December 2020‐January 2021) among a sample of Spanish RN (n = 420). NPV were assessed using the Nursing Professional Values Scale (NPVS‐R), comprising 26 items grouped into five factors: caring, activism, trust, professionalism, and justice. Perceived stress, anxiety, and depression were measured by the Perceived Stress Scale (PSS‐14) and the Hospital Anxiety and Depression Scale (HADS). Adjusted linear regressions were used to estimate b coefficients for the associations between NPV scores and the three mental health indicators. Results. The fully‐adjusted analysis, including sociodemographic and occupational variables, revealed that higher activism scores were associated with higher scores of stress (b coefficient: 0.46; 95% confidence interval: 0.03–0.88; p value: 0.035), anxiety (0.24; 0.05–0.43; 0.014), and depression (0.19; 0.01–0.36; 0.035). No other NPV was associated with mental health. Conclusion. Organizational policies and programs should be established to protect the most activist RNs and to mitigate the potential detrimental effect of activism on mental health at times and/or circumstances of high workloads and personal stress.