•Adapted pearl millet hybrids could contribute to food security in West Africa (WA).•Heterosis in population hybrids indicated great potential for hybrid breeding in WA.•Hybrids based on inter-country crosses did not differ from intra-country crosses.•Lack of natural heterotic groups requires systematic combining ability studies. Pearl millet (Pennisetum glaucum (L.) R. Br.) is an important hybrid crop in India. However, to date limited pearl millet hybrid development has been undertaken in West Africa (WA), which is the center of pearl millet origin and diversity and where this crop is most important outside India. Using a diverse set of WA pearl millet germplasm, objectives of this study were to determine the superiority of population hybrids over open-pollinated varieties for agro-morphological and agronomic traits in WA pearl millet germplasm; and (ii) to derive strategies for pearl millet hybrid breeding in WA, based on quantitative-genetic parameters, combining ability and heterotic patterns among geographically close versus distant pearl millet populations. A 10×10 factorial mating design was performed with four parental OPVs from each of five WA countries. The 100 population hybrids and their parents were tested for 14 traits at six locations in one year, thereby using contrasting locations to indirectly sample the rainfall variability inherent to WA pearl millet production environments. Grain yield showed an average panmictic midparent heterosis (PMpH) of 16.7%, ranging from −26 to 73%. The mean grain yield of hybrids based on inter-country crosses did not differ significantly from intra-country crosses. Geographic distance between parents was positively correlated with hybrid grain yield (r=0.31), but not with PMpH . Some crosses between accessions from Niger/Nigeria and Senegal were outstanding. Predictability of population hybrid performance for grain yield was moderate based on midparent values (r=0.43) and slightly better based on general combining ability (GCA) (r=0.56). Overall, pearl millet hybrid breeding in WA seems very promising, but there do not seem to be clear “natural” heterotic groups among WA pearl millet landraces. Such heterotic groups as the basis of sustainable hybrid breeding need rather to be created systematically, by building on existing combining ability patterns and aiming to maximize combining ability between the groups.