Despite the fact that Manus Province is the most geographically isolated province of Papua New Guinea, research shows that the acculturation process, common among minority indigenous groups around the globe, has had detrimental effects on maintaining knowledge and customs. Analysis of ethnobotanical knowledge among the indigenous population of Manus was undertaken in an attempt to compare, contrast, and draw conclusions regarding factors in maintaining indigenous knowledge of the local flora. Four levels of knowledge (plants recognized, identified, identified as useful, and identified as medicinally useful) were used to examine the relationships between knowledge of the local flora and physical, geographical, and social variables of informants. Results showed significant differences in ethnobotanical knowledge based on informant gender, age, cultural subclass, and habitation locality. Low levels of medicinal plant knowledge were found among the Manus due to acculturation, supporting the theory that medicinal plant knowledge is particularly vulnerable to loss.