Background: Although family caregivers (FCs) play an important role in the care provided to incurable cancer patients in our region, little is known about the burden they experience. Objectives: This study was conducted to determine the prevalence of caregiver burden (CB) among FCs of incurable cancer patients in two Eastern Mediterranean countries and to identify factors that may be associated with significant CB. Methods: The study included 218 FCs, 165 from Egypt and 53 from Saudi Arabia. The 22-item Zarit Burden Interview (ZBI-22) was used to assess caregiver burden CB. Significant CB was defined as a ZBI-22 score ≥ 21. The assistance with basic ADLs was classified into 3 levels according to FCs’ assistance with early/middle/late-loss basic ADLs. The relationship between CB and the assistance with ADLs and other factors was studied. Results: The mean (SD) ZBI-22 score among FCs was 23.4 (9.3) and the majority (128/218, 59%) had significant CB. Eighty-nine percent of FCs assisted with at least one basic ADL. Assistance with late-loss basic ADLs, best supportive care treatment plan and poorer performance status were associated with higher CB (p < 0.0001, =0.018 and = 0.005). However, in logistic regression analysis, only assistance with late-loss ADLs was independently associated with significant CB (OR = 3.4 [95%CI:1.2–9.7], p = 0.024). Conclusion: A substantial proportion of FCs of incurable cancer patients in our region experience significant CB. Family caregivers assisting with late-loss basic ADLs are at risk of significant CB and should be routinely screened for CB.