Background <p>Family caregiver (FC) of persons with dementia (PWD) are increasingly affected by mental and physical health which leads to poor quality of life (QoL). Telephone-based interventions offer flexible solution to support caregivers of PWD but the effectiveness needs further evaluation. This study aimed to assess the effectiveness of a telephone-based intervention in improving QoL among FC of PWD and to examine the role of caregiver burden as a mediating factor.</p> Methods <p>A randomized control trial study was conducted involving 121 FCs, divided into intervention (<i>n</i> = 60) and control (<i>n</i> = 61) groups. The intervention group received a 10-week intervention by the healthcare professionals via telephone. QoL were measured using the validated Malay version of Control, Autonomy, Self-Realization and Pleasure (CASP-19) at baseline (T0) and endline (T1). Intention-to-treat (ITT) analysis was performed to determine the independent effect of the intervention on QoL, and mediation analysis was conducted using the multiple linear regression and bootstrap analysis.</p> Results <p>Participants in the intervention group showed a statistically significant improvement in QoL (β = 5.00, 95% CI 2.21–7.78, <i>p</i> = 0.001). Mediation analysis revealed that caregiver burden mediated the relationship between the telephone-based intervention and QoL. Additionally, reduction of caregiver burden was observed to mediate the relationship between telephone-based intervention and reduced anxiety symptoms.</p> Conclusion <p>Telephone-based intervention was effective in improving the QoL among FCs of PWD. The findings also suggest that caregiver burden plays a mediating role in this process, underscoring the need for policymakers to integrate burden-reduction training into future programs.</p> Trial registration <p>ISRCTN14565552.</p>