Past studies have shown that acculturation and self-efficacy can affect respite care knowledge, which are notable issues among immigrant caregivers due to the rapid increasing aging family members. The aim of this study was to investigate relationships among acculturation, self-efficacy, and respite care knowledge in immigrant caregivers, and to determine the mediating effects of self-efficacy on the relationship between acculturation and respite care knowledge. A cross-sectional design was used. We enrolled 134 female immigrant caregivers who had married Taiwanese men and lived with care recipients who used LTC services. Based on Baron and Kenny’ mediating analytic framework, multiple regression and Sobel tests were used to examine whether self-efficacy mediated the relationship between acculturation and respite care knowledge. The findings showed that after controlling for confounding factors, acculturation and self-efficacy separately affected respite care knowledge (B = 0.229, standard error (SE) = 0.084; B = 0.123, SE = 0.049, respectively). Acculturation had a positive impact on respite care knowledge through self-efficacy (B = 0.181, SE = 0.084). Therefore, self-efficacy partially mediated the effect of acculturation on respite care knowledge, and accounted for 20.9% of the total mediating effect in this study. Acculturation predicted immigrant caregiver’ respite care knowledge partially through self-efficacy. The association between acculturation and respite care knowledge was partially mediated by immigrant caregivers’ self-efficacy. As a result, it was proposed that boosting self-efficacy could increase and drive immigrant caregivers’ respite care knowledge. To assist this population in obtaining enough resources, targeted educational programs to promote immigrant caregivers’ self-efficacy should be designed and implemented. Furthermore, health care practitioners should be aware of the relevance of immigrant caregivers’ acculturation.