The university period can be stressful for most students. It may be due to exposure to various stressors. Objectives: To establish the prevalence and factors associated with high perceived stress among university undergraduates in south-western Saudi Arabia. A self-administered survey was conducted among a representative sample of King Khalid University students through a cross-sectional study. Data obtained included socio-economic, academic characteristics, and grade point average (GPA) scores. Stress was assessed using the Perceived Stress Scale. This study included 2467 students. The average Perceived Stress Scale score was 19.13 ± 6.56, which was notably higher ( P = .02) among health care undergraduates (19.45 ± 6.49) compared to others (18.85 ± 6.61). High perceived stress prevalence rate was 12.7% (13.6% in health care institutions and 12.0% in non-healthcare institutions). Multivariable analysis revealed that high perceived stress was considerably greater among females (adjusted odds ratio [aOR] = 2.35, 95% confidence interval:167–3.30), smokers (aOR = 1.65), those with an unsatisfactory income (aOR = 3.10), and healthcare students (aOR=1.33). In contrast, it was negatively associated with the GPA score (aOR= 0.77). High perceived stress is a substantial problem among university students. Female students and healthcare students are at a greater risk. High stress is correlated with smoking, lower GPA scores, and perceived insufficient family income.