We investigate changes in lifestyle, physical, and mental health during the confinement period of the first and second waves of COVID-19, as well as their relation to sociodemographic parameters and confinement status. Sociodemographic data and information regarding changes in their lifestyle behavior and changes in body weight and physical activity (PA) were collected. The SF-36 questionnaire was implemented for measuring the domains related to physical health (PH) and mental health (MH). The growth frequency of weight gain in the Mexican (4.8%) and Chilean (10.9%) populations was observed during the second wave. The MH component decreased in the Mexican and the Chilean population (p < 0.05). Moreover, the MH decreased significantly according to the degree of confinement (p < 0.01). Although some sociodemographic factors were related to the presence of a very low score (<50 scores) for the MH component during the first wave, it is perceived as a higher relative risk during the second wave in both populations. The long confinement due to COVID-19 is associated to negative changes in nutritional and physical lifestyle behavior, affecting mainly the MH component.