Background: The association between caregiver burden and the physical frailty of older adults has been the object of previous studies. The contribution of patients’ dispositional optimism on caregiver burden is a poorly investigated topic. The present study aimed at investigating whether older adults’ multidimensional frailty and optimism might contribute to the burden of their family caregivers. Methods: The Caregiver Burden Inventory was used to measure the care-related burden of caregivers. The multidimensional frailty status of each patient was evaluated by calculating a frailty index, and the revised Life Orientation Test was used to evaluate patients’ dispositional optimism. The study involved eighty family caregivers (mean age 64.28 ± 8.6) and eighty older patients (mean age 80.45 ± 7.13). Results: Our results showed that higher frailty status and lower levels of optimism among patients were significantly associated with higher levels of overall burden and higher burden related to the restriction of personal time among caregivers. Patients’ frailty was additionally associated with caregivers’ greater feelings of failure, physical stress, role conflicts, and embarrassment. Conclusion: Understanding the close connection between patient-related factors and the burden of caregivers appears to be an actual challenge with significant clinical, social, and public health implications.