Abstract Background Health-related quality of life (HRQOL) is a multidimensional construct that refers to an individual’s self-perceived well-being. This study used the revised Wilson and Cleary HRQOL model to investigate the associations among oral symptoms, oral health-related quality of life (OHRQOL), and HRQOL of people living with HIV/AIDS (PLWHA) in Malaysia. Methods A total of 121 PLWHA receiving medical care in Kota Bharu (Kelantan, Malaysia) participated in this cross-sectional study. The Malay version of the short Oral Health Impact Profile (S-OHIP(M)) and the Malay version of the 36-item Medical Outcome Study Short Form (SF-36) were used to assess OHRQOL and HRQOL, respectively. A higher S-OHIP(M) score indicates greater oral impact and worse OHRQOL; a higher SF-36 score indicates better HRQOL. An additional structured self-administered questionnaire was used to obtain other variables of interest from the participants. Results Most participants had at least one oral symptom (69.4%), and the most common oral symptom was a cavitated tooth (55.4%). The prevalence of oral impacts was 33.9%, and the mean S-OHIP(M) score was 8.8 (SD = 7.92). The mean S-OHIP(M) score was significantly higher in participants who had toothaches, cavitated teeth, gum abscesses, and bad breath. In addition, participants with lower S-OHIP(M) scores had significantly higher scores in all SF-36 domains. Conclusions Our study provides evidence for an association among oral symptoms, OHRQOL, and HRQOL in PLWHA from Malaysia. In particular, the presence of oral symptoms was significantly associated with more severe oral impacts and poorer OHRQOL. The presence of less severe oral impacts was associated with a better HRQOL.