Background: Many studies have investigated factors associated with quality of life (QoL) in nursing home residents with dementia. Both pain and neuropsychiatric symptoms (NPS) are clinically relevant and individually associated with a lower QoL; however, there are no studies that investigated pain and NPS together in relation to QoL. Purpose: In this study, we explored the relationship of pain and NPS with QoL in nursing home residents with dementia by investigating the association between pain concurrently with NPS, and QoL. Methods and Patients: Secondary data analyses of cross-sectional data from 199 residents were collected by observations at dementia special care units of 10 nursing homes. QoL was measured with Qualidem, pain with the Mobilization Observation Behavior Intensity Dementia (MOBID-2) Pain Scale and NPS with the Neuropsychiatric Symptoms Inventory. The relation of pain and NPS to QoL was studied using multiple linear regression analyses. Analyses were adjusted for age, sex, activities of daily living, comorbidity, medication use, and dementia severity. Results: Regression models with pain and NPS, showed no independent relationship between pain and QoL subdomains, but NPS, in particular agitation and depressive symptoms, were significantly associated with lower QoL subdomain scores. Agitation was related to lower scores on the subdomains "relationship" [95% confidence interval (CI), -0.083 to -0.059], "positive affect" (95% CI, -0.037 to -0.013), "restless tense behavior" (95% CI, -0.003 to -0.004), and "social relations" (95% CI, -0.033 to -0.009), whereas depression was related to lower scores on the subdomains "positive affect" (95% CI, -0.054 to -0.014), "negative affect" (95% CI, -0.114 to -0.074), "restless tense behavior" (95% CI, -0.075 to -0.025), and "social relations" (95% CI, -0.046 to -0.002). Conclusions: Only NPS were significantly associated with QoL in nursing home residents with dementia. Further longitudinal research is needed to estimate the nature of the relationship between pain, NPS, and QoL.