Sense of coherence (SOC) is a psychological factor that contributes to mental health maintenance under stressful environment. Likewise, level of SOC might affect mental health among healthcare workers during the COVID-19 pandemic differently. In this study, we investigated the relationships between lifestyle changes and mental health (General Health Questionnaire-12: GHQ-12) among different level of SOC (weak, moderate, or strong by SOC-13). The data of 898 healthcare workers from cross-sectional survey dataset were extracted and analyzed. As results, based on GHQ-12 score, 86.1% of 244 participants with weak SOC, 60.1% of 606 participants with moderate SOC, and 31.3% of 48 participants with strong SOC had poor mental health. Both SOC levels and lifestyle changes (except alcohol consumption) had significant main effects on the GHQ-12 score. Analysis on the association between lifestyle changes and mental health status stratified by SOC level reveled that among participants with weak SOC, those who increased their leisure and activity time had reduced odds of poor mental health than those who made no changes (OR: 0.08, CI: 0.01 to 0.64). Healthcare workers with weak SOC were at risk of poor mental health during the COVID-19 pandemic, and lifestyle changes may improve their mental health.