To mitigate against the possible adverse effects of stress among nurses due to the COVID-19 outbreak, we designed a 12-week mind-body based online intervention program to promote well-being and prevent stress-related disorders such as burnout. Our study aimed to compare the impact of the intervention on perception of stress, negative emotions, burnout, mindfulness, resilience, and well-being at pretest and 6 months post-intervention and to compare the effect among nurses working at two different hospitals. We conducted an uncontrolled trial using a convenience sample of nurses working at two hospitals in Mexico: one designated to treat confirmed COVID-19 patients (COVID-hospital) and the other whose patients had a negative COVID-19 test on admission (Non COVID-hospital). The 12 week online intervention consisted of 36 mind-body based micropractices, with subjective well-being as the primary outcome. Secondary outcomes were health perception, resilience, mindfulness, negative emotions, stress, and burnout. A pretest survey was completed by 643 nurses. Of the remaining valid responses, 82% were women, with a mean age of 34.8 (SD = 8.95) years old. For the analysis two groups of nurses were sampled by cluster: a COVID-hospital group of 429 (67%) nurses, and a non-COVID Hospital group of 214 (33%) nurses. The proportion lost to follow-up was 71% at postest (n = 188) and 42% at 6 months follow-up (n = 371). At pretest, non-COVID hospital nurses had lower subjective well-being and higher burnout than their COVID hospital counterparts. At postest, non-COVID hospital nurses displayed more negative emotions than their COVID hospital peers. At 6 months post-intervention, nurses experienced improved mindfulness, reduced negative emotions and stress, but a decrease in subjective well-being and resilience. Nurses working at the non-COVID hospital had significantly higher mean scores for burnout than those working at the COVID hospital. The results of our study suggest that our online mind-body interventions can help to reduce stress and negative emotions, yet the effects on subjective well-being and resilience are uncertain. Further research is needed to gain a better understanding of their potential mechanisms and the associated efforts of such online interventions. ClinicalTrials.gov, NCT05515172.