This study aimed to evaluate denture care and hygiene and oral health-related quality of life (OHRQoL) among complete denture (CD) wearers in the Eastern Province of Saudi Arabia. This cross-sectional study was conducted on CD wearers in the Eastern Province of Saudi Arabia. A pre-tested questionnaire was administered among study participants. Questionnaire was divided in three sections: (1) patients' demographic data, (2) awareness and maintenance of CD and (3) OHRQoL. Independent sample t-test and one-way ANOVA test were performed. The study included data of 300 participants with 71% of males and 28% of females. Majority of participants (82.7%) cleaned CD daily, removed CD while sleeping (88.0%) and knew that unhygienic dentures can cause oral infection (92.7%). Only 19.3% used denture cleansing tables, 41% used toothpaste, and 60.7% rinsed CD with water. Regarding OHIP-DENT domains, highest score was for functional limitation domain (2.20 ± 1.67) and the lowest for handicap domain (0.94 ± 1.09). The mean OHIP-DENT score of the sample was 12.02 ± 8.52. Females (p = 0.006), participants below 65 years of age (p = 0.029), non-Saudis (p = 0.042), those with university education (p = 0.030) and low monthly income (p = 0.045) and participants who visited dentist due to problem with CD (p = 0.041) demonstrated significantly higher mean OHIP-DENT score. Majority of participants demonstrated appropriate denture care behaviours because they were aware of the importance of denture care and hygiene. Female gender, age below 65 years, non-Saudi nationality, university education, low monthly income and visiting dentist due to problem were related to poor OHRQoL.