The study aimed to characterize and understand the difficulties experienced by informal caregivers from a bio-psychosocial and environmental perspective, taking into account the socio-demographic and health characteristics of the informal caregiver and the person cared for, quality of life, perceived burden, social support, and the impact of the COVID-19 pandemic on the informal caregiver and the person cared for. The participants were 371 informal primary caregivers, 80.9% female, aged between 25 and 85 years, mean 53.17 (SD = 11.45) years. Only 16.4% of the informal caregivers benefited from monitoring and training for informal caregiver skills; 34.8% received information on the rights of the person being cared for; 7.8% received advice or guidance on the rights and duties of the informal caregiver; 11.9% of the caregivers benefited from psychological support; and 5.7% participated in self-help groups. A convenience sample was used, and data were collected via an online questionnaire. The main findings show that the major difficulties experienced by caregivers are related to social constraints, the demands of caring, and the reactions of the person cared for. The results reveal that the burden of the main informal caregivers is explained by the level of education, quality of life, level of dependence of the person cared for, level of difficulties, and social support. The COVID-19 pandemic impacted caregiving by increasing the perceived difficulty of accessing support services, such as consultations, services, and support; causing distress feelings in the caregiver, such as, anxiety and worry; increasing the needs and symptoms of the person cared for; and increasing the degree of isolation, for both, the informal caregiver and the person cared for.