As the global population ages, frailty, which has been shown to affect and predict the quality of life (QoL) of older adults, has become a central issue. The aim of this study was to explore the mediating effects of daily physical activity (DPA) and healthy life self-efficacy (HLSE) on the relationship between frailty and QoL in older adults using a serial multiple mediation model. The cross-sectional study was conducted among 210 community-dwelling older adults in Taiwan. Data were collected using the Taiwanese version of the Tilburg Frailty Indicator, the EuroQoL visual analog scale, the Kihon Checklist, and the Chronic Disease Self-Efficacy Scales. The PROCESS macro for SPSS based on the bootstrap method was used to determine the mediating effects of DPA and HLSE on the relationship between frailty and QoL. The results showed that frailty was found to have both direct and indirect effects on QoL. As predicted, DPA and HLSE partially mediated the relationship between frailty and quality of life (DPA: B = −0.71, p < 0.001; HLSE: B = −0.32, p < 0.001). In addition, serial mediation analyses indicated that the association between frailty and QoL was partially mediated by DPA and HLSE in a sequential manner (B = −0.16, p < 0.001). The serial mediation has a causal chain linking DPA and HLSE, with a specified direction of causal flow. According to the results of the serial multiple mediation model, the elderly should be encouraged to continue their activities in daily life, which not only improves self-efficacy and confidence in maintaining health but also reduces the negative impact of frailty on QoL.