<b><i>Introduction:</i></b> This study aimed to compare the mental health, quality of life, and caregiving burden between male and female informal caregivers of older adults (≥60 years) during the second wave of the COVID-19 pandemic in Germany. <b><i>Methods:</i></b> The sample consisted of 301 female and 188 male informal caregivers of older adults in need of care (≥60 years). Data were used from a cross-sectional study in March 2021 that questioned a representative sample of adults aged 40 years and older from Germany. Information on informal care provision, mental health (depressive and anxiety symptoms), caregiving burden, and quality of life was assessed for the period between December 2020 and March 2021. Regression analyses, adjusted for (1) the sociodemographic background and health of the caregivers, (2) the caregiving time and caregiving tasks, and (3) the perception of impairment and danger posed by the pandemic, were conducted. <b><i>Results:</i></b> Findings of the fully adjusted model indicated a higher level of anxiety and lower quality of life among female caregivers, compared to male caregivers. Gender differences in depression and caregiver burden were not significant in analyses that controlled for care tasks and time. Moderator analyses indicated that gender differences in caregiver’s anxiety levels were influenced by the danger perceived to be posed by the pandemic: among men the danger to the care recipient, and among women the danger to themselves, increased anxiety. <b><i>Conclusion:</i></b> Female informal caregivers were more negatively affected than male informal caregivers during the pandemic, as indicated by higher levels of anxiety and lower quality of life. Gender differences in anxiety depended on the perceived danger posed by the pandemic. Thus, policy and pandemic measures should focus on gender-specific support of female caregivers who seem to be particularly vulnerable during the pandemic. More caregiver-specific support and information around protecting themselves and their care recipients are recommended. Also, further research on gender differences in care performance and their relation to psychosocial health outcomes is recommended.