The COVID-19 pandemic has led to a surge of mental health disturbances and the subsequent use of various mind-body therapies. Although evidence supports the benefits of yoga for mental health in a variety of disease states, information on its effects among healthcare workers during the COVID-19 epidemic is scarce. Therefore, this study evaluated and compared the efficacy of relaxation to music and yoga nidra on the mental health of frontline healthcare workers during the pandemic. This open-label randomized trial was conducted at a Level III COVID-19 care center. In the Relaxation-to-Music Group, participants received deep relaxation music, whereas those in the Yoga Nidra Group performed yoga nidra practices; both interventions were delivered through a YouTube platform and were to be done daily for 30 minutes during the healthcare workers’ 2-week duty periods. The primary outcomes were measured using scores of the Patient Health Questionnaire (PHQ)–9, Generalized Anxiety Disorder (GAD)–7 scale, and Insomnia Severity Index (ISI) at the end of the duty period. A total of 79 healthcare workers were randomly divided into two groups: (1) Relaxation-to-Music (n = 40) and (2) Yoga Nidra (n = 39). Demographics; clinical characteristics; and PHQ-9, GAD-7, and ISI scores of the two groups were comparable at baseline. In the Yoga Nidra Group, PHQ-9 scores decreased significantly (5.17 ± 4.25 to 3.03 ± 2.40, p = 0.002) compared to the Relaxation-to-Music Group (5.68 ± 4.73 to 4.34 ± 2.90, p = 0.064). Similarly, GAD-7 scores decreased significantly in the Yoga Nidra Group (4.93 ± 3.27 to 2.33 ± 2.56, p < 0.001) compared to the Relaxation-to-Music Group (4.84 ± 3.94 to 4.03 ± 3.56, p = 0.123). ISI scores also decreased significantly in the Yoga Nidra Group (6.10 ± 3.53 to 3.03 ± 2.88, p < 0.001) compared to the Relaxation-to-Music Group (6.09 ± 5.37 to 5.93 ± 5.95, p = 0.828). In this study, yoga nidra practice was more helpful than relaxation to music in reducing depression, anxiety, and insomnia among frontline COVID-19 healthcare workers during their duty periods.