The aim of the present cross-sectional study was to analyze the differential impact of the first COVID-19 lockdown (3 April 2020) on stress, health practices, and self-care activities across different Hispanic countries, age range, and gender groups. One thousand and eighty-two participants from Spain, Chile, Colombia, and Ecuador took part in this study. Irrespective of the country, and controlling for income level, young people, especially females, suffered a greater level of stress, perceived the situation as more severe, showed less adherence to health guidelines, and reported lower levels of health consciousness, in comparison to their male peers and older groups. However, in the case of self-care, it seems that older and female groups are generally more involved in self-care activities and adopt more healthy daily routines. These results are mostly similar between Colombia, Ecuador, and Spain. However, Chile showed some different tendencies, as males reported higher levels of healthy daily routines and better adherence to health guidelines compared to females and people over the age of 60. Differences between countries, genders, and age ranges should be considered in order to improve health recommendations and adherence to guidelines. Moreover, developing community action and intersectoral strategies with a gender-based approach could help to reduce health inequalities and increase the success of people ́s adherence to health guidelines and self-care-promoting interventions. Future studies should be addressed to explore the possible causations of such differences in more cultural-distant samples and at later stages of the current outbreak.