Problem gambling among young people is now a public health challenge in sub-Saharan Africa. However, the behaviour remains understudied, particularly, among rural-dwelling young people in countries within the subregion. We aimed to estimate the 12 months prevalence of problem gambling and to describe the overall and gender differences and commonalities in personal factors and social adversities associated with problem gambling among adolescents in rural Ghana. We conducted a cross-sectional survey involving a random sample of 1101 in-school adolescents aged 10–19 years in a rural district in Eastern Ghana; we used the DSM-IV-Multiple Response-Juvenile (DSM-IV-MR-J) questionnaire to assess problem gambling during the previous 12 months. Personal lifestyle and psychosocial variables were assessed using adopted items from the 2012 WHO–Global School-based Student Health Survey. Overall, three in 10 adolescents (3 in 10 females; 4 in 10 males) in rural Ghana reported problem gambling in the previous 12 months. Female adolescents who experienced problem gambling were more likely to report family-related social adversities, while adolescent male problem gambling was associated with school-related factors and interpersonal factors outside the family context. Regardless of gender, sexual abuse victimisation was associated with three times increase in the odds of experiencing problem gambling. Relative to the prevalence of gambling among adolescents in urban contexts in other countries within sub-Saharan Africa, the estimates of problem gambling among in-school rural adolescents in Ghana are higher. Although further studies are needed to understand the nuances of the behaviour, the evidence of this study underscores the need for general and targeted health promotion, intervention and prevention efforts to mitigate the family, school, and interpersonal social adversities associated with adolescent problem gambling in rural Ghana.