Xaysomboun province has some of the lowest health indicators in Lao People’s Democratic Republic (PDR). This cross-sectional study aimed to determine the vaccination, susceptibility and exposure status of the population to hepatitis B virus (HBV), measles, rubella, and tetanus. Participants aged 5 years and older were randomly selected from four districts. From each enrolled participant, demographic data and 5 mL of blood sample were taken. HBV surface antigen (HBsAg) and antibodies against HBV, measles, rubella, and tetanus were detected by ELISA. A total of 363 participants (age 5 to 80 years) were included. HBV exposure, as determined by anti-HBV core (anti-HBc) antibodies, was 56.2% overall, and was significantly higher among those aged ≥21 years (78.1%). HBsAg was detected in 9.4% overall and increased to 20% in ages 31–40 years. Only 13.8% of participants had serology indicative of vaccination (anti-HBs positive, anti-HBc negative). Seroprotection against measles was 74.6% overall but only 41.7% in children aged 5–10 years. Anti-rubella IgG was 94.2% overall and high in all age groups. Tetanus seroprevalence was only 47.4% overall but significantly higher in females aged 31–40 (75.6%). We suggest strengthening of routine and booster HBV, measles, and tetanus vaccine coverage in Xaysomboun province.