Very few studies have examined quality of life (QOL) in elderly carers of orphaned children in African settings. This study explored sociodemographic factors and health-related characteristics that influence QOL of grandparent carers in Zimbabwe. A cross-sectional study stratified by district was done to collect information on socioeconomic factors, health-related characteristics, and QOL of grandparent carers (N = 327; age: M = 62.4, SD = 11.2). Data were collected on socioeconomic factors, self-perceived health, health care access, chronic disease condition, health insurance status, types of health care services, and medications taken using the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF). Bivariate and multivariate analyses were used to investigate the associations between QOL and the predictor variables. Caregivers’ level of education (odds ratio [OR] = 3.0; confidence interval [95% CI] = [1.0, 27]), fostering orphans only (OR = 0.4; 95% CI = [0.2, 0.7]), self-perceived health (OR = 10.2; 95% CI = [4.5, 25]), medical insurance (OR = 9.8; 95% CI = [1.9, 54]), and satisfaction with health care services (OR = 2.2; 95% CI = [1.2, 4.4]) were associated with QOL, after adjusting for all influencing factors. The results confirm that QOL is compromised by specific demographic and self-rated health characteristics. Thus, eradicating poverty and providing services and changing caregiver’s perceptions about self-rated health may enhance QOL among grandparent caregivers.