Introduction: Despite the increased number of homeless people in Malaysia, there is limited information on their oral health status and oral health-related quality of life (OHRQoL). This study aims to investigate the impact of caries experience, dental anxiety, oral health (OH) knowledge, and OH behaviours on the OHRQoL of homeless adults in Malaysia, as well as to determine the mediation role of caries experience towards OHRQoL. Methods: A cross-sectional study involving homeless persons was conducted in five states in Malaysia. Dental caries was examined using Decayed, Missing and Filled Teeth (DMFT) index. Face-to-face interview was conducted to collect information about OH knowledge and behaviours, dental anxiety, and OHRQoL using validated questionnaires. Meanwhile, descriptive and bivariate analyses were conducted using SPSS. Partial least squares structural equation modelling (PLS-SEM) was performed to test the hypotheses of the conceptual model with the support of SmartPLS. Results: A total of 192 homeless people completed the questionnaire and oral examination. The majority were male (84.9%), with a mean age of 43.72 (SD = 11.6). The severity of OHRQoL impact (mean OHIP score) was 18.61(SD = 11.3). There were significant independent relationships between dental anxiety (β = 0.306, p < 0.001) and caries experience (β = 0.280, p < 0.001) on the homeless OHRQoL. It was found that the relationship between OH knowledge and OHRQoL was significantly mediated by caries experience. Conclusion: According to the structural model, caries experience, dental anxiety, and OH knowledge have significantly impacted the OHRQoL of the Malaysian homeless. These studied factors should be considered in the adoption of a holistic approach to improve the OHRQoL among homeless people in Malaysia.