Background/Objectives: Population aging poses many challenges to public health, highlighting loneliness and social isolation as severe problems that affect the physical and mental health of older adults. During the COVID-19 pandemic, these became aggravated. The objective of the present study was to assess the prevalence of loneliness and its relationship with social isolation, depression, cognitive deterioration, sleep quality, and the level of physical mobility and functioning of older adults in Health Area 3 of the Region of Murcia. Methods: A descriptive, observational, and cross-sectional study was performed. The inclusion criteria were age ≥ 65, living in Health Area 3 of the Region of Murcia, and not being institutionalized. The following variables were evaluated: sociodemographic variables, loneliness (UCLA scale), social isolation (DUFSS), depression (GDS), cognitive deterioration (Pfeiffer), sleep quality (PSQI), and mobility (Barthel index). A univariate and multivariate regression model was created to examine how the dependent variable was related to the independent variables. Results: A total of 102 older adults participated in the study. Of these, 31.4% perceived unwanted loneliness and 14.7% low social support. The multivariate regression analysis showed that social isolation, geriatric depression, and cognitive deterioration were significant predictors of loneliness. Conclusions: The findings highlight the importance of developing multifaceted interventions that address not only social isolation but also other interrelated factors such as depression, cognitive deterioration, and sleep quality. The strategies should be centered on community programs and support networks. It is fundamental to perform longitudinal studies to better understand the causal relationships between these variables.