Background: The global COVID-19 lockdown restricted daily routines due to the psychological fear of infection, which imposed an unknown universal threat on female college students, affecting physiological health and well-being. However, scant information concerning the efficacy of yogic practice on female college students during the stressful COVID-19 pandemic situation is available. Methods: In a randomized controlled trial (n = 74, age = 21.65 [4.05] y), a study was conducted with a well-conceptualized yogic module for 5 days/week for 3 months (40 min daily in the morning) among yogic volunteers. Pre–post analysis of anthropometric, physiological, and biochemical indices in pandemic-stressed female college students was done for the control and yoga groups. Results: After 3 months of yogic practice, significant reduction (P < .05) in heart rate (d = 0.64, meandiff = 5.43), systolic blood pressure (d = 0.59, meandiff = 5.32), cortisol (d = 0.59, meandiff = 6.354), and triglycerides (P < .01, d = 0.45, meandiff = 13.95) was observed. After yogic follow-up significant improvement (P < .01) in high-frequency (d = 0.56, meandiff = −7.3), total power (d = 0.46, meandiff = −1150) and time domain parameters of heart rate variability led to ameliorate the stress index. Superoxide dismutase (P < .01, d = 0.78, meandiff = 0.69), catalase (P < .05, d = 0.48, meandiff = −7.37), glutathione (P < .001, d = 0.83, meandiff = −4.15), high-density lipoprotein (P < .05, d = 0.48, meandiff = −11.07), and dopamine (P < .001, d = 0.97, meandiff = −135.4) values along with inflammatory markers (P < .001) significantly improved among yogic volunteers after regular practice. Conclusions: Our findings suggest that a 3-month well-conceptualized yogic intervention during COVID-19 may be considered as a prophylactic tool to improve female college students’ universal psychophysiological health by ameliorating autonomic functions, cardiometabolic risk factors, and immune metabolisms in an economical and environment-friendly manner.