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Inequality in South Africa is deeply rooted, and COVID-19 glaringly brought inequalities between families to the forefront. This study aimed to investigate factors associated with the above average stress levels of female primary caregivers in vulnerable families during the COVID-19 pandemic. A cross-sectional survey was undertaken among vulnerable families from October 2021 to February 2022. Above average scores were reported by approximately half of the respondents regarding stress from children/partners and stress related to financial issues. Fear of COVID-19, feeling depressed, COVID-19′s impact on daily life, lower education levels, being in a relationship and living together, and perceiving an increase in domestic violence were statistically significantly associated with above average stress from children/partners. Age, impact of COVID-19 on daily life, being in a relationship and living with a husband/partner, and running out of food during the past 30 days were statistically significantly associated with above average stress concerning finances. These results provide new insights that can assist policy makers and practitioners in supporting low-income families during times of crisis. Support should not just focus on practical aspects, such as the provision of food, but equally importantly, on emotional support and protection for female primary caregivers and their families. Future research should delve more deeply into causes of COVID-19-related stress in vulnerable families.