The global trend of advanced aging comes at the cost of amplified onset of age-related diseases. Dementia is a common multifactorial age-related neurodegenerative disorder, which manifests with progressive declines in cognitive functioning and ability to perform activities of daily living. As polices discourage institutionalized care, family members act as primary caregivers and endure increased vulnerability to physical and mental health problems secondary to care-related changes in life routine and relationships. Targeting clinically significant distress at earlier stages through valid brief measures may promote caregivers’ wellbeing and dementia care continuity/quality. This study aimed to determine the optimal cutoff score of the Depression Anxiety Stress Scale 8-items (DASS-8) in a convenience sample of 571 European caregivers (Mean age = 53 ± 12 years, Italian = 74.4%, Swiss = 25.6%) through three methods. K-means clustering classified the sample into high- and low-distress clusters based on DASS-8 score of 19. Receiver operator curve (ROC) analysis using 48 and 7 cutoffs of the Zarit Burden Interview (ZBI) and the Three-Item University of California, Los Angeles, Loneliness Scale-version 3 (UCLALS3), revealed two DASS-8 cutoffs (12.5 and 14.5, area under the curve (AUC) = 0.85 and 0.92, p values < .001, 95% CI 0.82–0.88 and 0.89 to 0.94, sensitivity = 0.81 and 0.78, specificity = 0.76 and 0.89, Youden index = 0.57 and 0.67, respectively). Decision modeling produced two DASS-8 cutoffs (9.5 and 14.5) for predicting low and high caregiving burden and loneliness, respectively. According to the median of all DASS-8 cutoffs (14.5) the prevalence of mental distress was 50.8%. Distress correlated with key mental problems such as burnout and loneliness—in path analysis, DASS-8 scores were predicted by the ZBI, UCLALS3, care dependency, and receiving help with care, especially among older, female, and spouse caregivers. Further diagnostic workup should follow to confirm psycho-pathogenicity among caregivers with DASS-8 scores above 14.5. Investigations of the DASS-8 in other countries/populations may confirm the validity of this cutoff score.