International students in the United States are confronted with a wide range of challenges and difficulties as they move to a new country and need to adapt to a new cultural, social, and academic environment. This study examined the relationship between acculturation orientation, or how these cultural changes are addressed, sources of social support, and the level of acculturative stress these students experience. Data was collected using an on-line survey from international students at six public universities in Missouri, Oklahoma, Texas, and Iowa. Statistical analysis was conducted on the data collected from the 648 students who participated in the study. Descriptive statistics, group comparisons, and a regression model were employed to summarize and test the study’s hypotheses. Correlational analysis indicated that lower levels of acculturative stress were associated with both positive cultural identification with both the home and host culture, as well as the presence of a wide network of social support, while increased levels of acculturative stress were found to be related primarily to higher levels of perceived discrimination and higher levels of mood and anxiety disturbances. Analysis of group differences found that students with positive home and host cultural identifications, as well as students with broad-based social support, experienced statistically significant lower levels of acculturative stress than other groups. A prediction model was developed, although only perceived level of English language ability, perceived discrimination, levels of mood and anxiety disturbance, positive host culture identification, and host country social support were found to be statistically significant predictors. The study findings highlight the importance of both positive cultural identification with both the home and host culture, as well as the positive association with higher levels of social support on mitigating the level of acculturative stress international students experience. The findings have implications for mental health professionals counseling international students in the United States to better understand and thereby develop more effective therapeutic interventions in their work with international students. Suggestions for future research are also indicated.