Low birth weight (LBW) infants are at risk for vertical and horizontal transmission of COVID-19. A mother’s ability to prevent infection in LBW infants is decided by their knowledge, self-efficacy, and abilities of the mother in carrying out infection-prevention care. This study aimed to analyze the relationship between mothers’ knowledge and self-efficacy with their ability to prevent infection in LBW infants during the COVID-19 pandemic. This study used a correlational design. This study included 84 respondents who were selected through purposive sampling in the perinatology room. The statistical test used was the Spearman Rho. The outcomes confirmed a relationship between a mother’s knowledge (r = 0.249; p = 0.022) and self-efficacy (r = 0.313; p = 0.004) with the mother’s ability to prevent infection in LBW infants. The level of strength of the positive relationship between a mother’s knowledge and the mother’s ability to prevent infection in LBW infants is 0.249, or very vulnerable. The level of the strength of the positive relationship between maternal self-efficacy and the mother’s ability to prevent infection in LBW infants is 0.313, or sufficient. Therefore, increased knowledge and self-efficacy of mothers may have an impact on increasing the ability of mothers to prevent infection in LBW.