Indigenous knowledge (IK) can provide useful information on local people's activities within environmental contexts. For countries vulnerable to climate change as Vietnam, research on IK might assist in revealing information about local people's responses to environmental stresses and potentially support decision-making. To enrich the study context in this field, this study aims at determining the IK of peanut cultivation of the Khmer ethnic groups. The study site is in the mountainous area in An Giang province, Vietnam, where the Khmer people are located. The methods of documentary collection, focus group discussion, semi-structured interviews, and experiments were applied in this study. The investigation results showed the innovation of local people in the cultivation. For instance, applying cow manure to a sandy soil can reduce chemical fertilizers and improve peanut yield. The IK reported that the application of the broadcasting method could achieve the cultivation economic profit approximately 2.5 times higher than the dibbling method. The former method is mostly preferred due to its time/labor saving and the growing aged population in the study location. The experimental results indicated that the combination of indigenous and scientific knowledge in peanut cultivation, such as chemical fertilizer application, crop calendar, crop rotation, and varieties, could bring high economic efficiency, improve soil nutrients, and ability to adapt to climate change. The research approaches in this study comprehensively revealed the IK, which can be potentially applicable to similar studies.