The COVID-19 pandemic has highlighted the importance of informal care and shown that women continue to shoulder the brunt of responsibilities in this area. In this study, we analyzed differences in caregiving and self-perceived health in a group of informal male and female caregivers 1 year into the COVID-19 pandemic. We performed a cross-sectional survey of 261 informal caregivers (165 women and 96 men) in two regions of Spain using computer-assisted telephone interviewing between February and April 2021. We performed descriptive, bivariate, and multivariate analyses to calculate the odds of poor self-perceived health according to different caregiver, care recipient, and caregiving characteristics. We also analyzed the perceived effects of the pandemic on caregiving, caregiver health, and other aspects of life. Compared with male caregivers, female caregivers were more likely to experience increases in caregiving intensity and burden and a decline in self-perceived health as a result of the pandemic. Men providing high-intensity care, however, also reported deteriorated health. Men experienced fewer reductions in informal support, a factor that exerted a protective health effect. Women, by contrast, experienced a reduction in all support systems and in this case, a third-level education exerted a protective effect. Our results provide key insights that should be taken into account to design gender-based interventions aimed at supporting already stretched and burdened caregivers. A greater sharing of responsibilities and more resources are needed.