This study examined the relationships between risk (i.e., gambling cognitions, gambling urges, psychological distress) and protective factors (i.e., life satisfaction, resilience, gambling refusal self-efficacy) and problem gambling among 310 Singaporeans aged between 18 and 73 years. Data on demographics, risk and protective factors, and gambling behavior were collected through electronic and paper surveys. Hierarchical multiple regression was employed to assess the contributions of the risk and protective factors in predicting problem gambling. Three risk factors (i.e., gambling cognitions, gambling urges, psychological distress) and two protective factors (i.e., resilience, gambling refusal self-efficacy) were found to significantly and uniquely predict problem gambling. Furthermore, the risk factors significantly interacted with the protective factors to moderate gambling severity. Gambling refusal self-efficacy shows significant protective effects against problem gambling, while the effects of resilience on gambling vary across settings. Both factors need to be taken into account in the understanding of problem gambling.