The decline in agricultural productivity and income has been a major problem in developing countries, and smallholder farmers are practicing alternative land uses to improve their livelihoods. This study assesses the socio-ecological benefits and determinants of Rhamnus prinoides-based agroforestry practices by smallholder farmers in Tigray, Ethiopia. Socioeconomic data were collected from 191 randomly selected households in three villages with extensive R. prinoides agroforestry practices. Descriptive and quantitative statistics were employed to analyze socioeconomic implications and determinants of the extent of the practice. Enterprise-specific budget analysis was conducted to assess the profitability of the practice. The main purposes for practicing R. prinoides agroforestry included maximizing (98.1%) and stabilizing (63%) production and income, and coping with seasonal fluctuations (75%), and accruing sociocultural (54%) and ecological (37%) benefits by diversifying and commercializing the production system. This agroforestry practice insured land use rights (54%) and provided employment opportunities for both the practicing farmers (98.1%) and the local community (43.4%). Notably, females played a more significant role than males in R. prinoides product harvesting (97.5%) and income administration (83.8%). The net returns to land, labor, and capital of R. prinoides agroforestry were 300%, 80%, and 12% higher, respectively, compared to wheat mono-cropping. Gender, age, family size, land ownership, farm size, farm fertility, number of farm parcels, and farmers’ wealth status were determinants of practicing R. prinoides agroforestry. Thus, scaling up similar practices that integrate trees/shrubs with valuable products and services that are socioeconomically and agroecologically suitable could enhance the socioeconomic well-being of smallholder farmers.