Background Post-traumatic stress disorder (PTSD) is the most commonly reported mental health consequence following traumatic events. However, little is known about how people with HIV cope with the PTSD burden in Lira city, northern Uganda. Materials and Methods This study was carried out in Lira District Health Centre IVs from February 10, 2022, to March 10, 2022. A facility-based cross-sectional study was employed among 390 people with HIV attending Lira Health Centre IVs. A consecutive sampling technique was used to select the sample size. Questionnaires were used to collect data. A binary logistic regression model was fitted to identify factors associated with independent variables, and AOR was employed to estimate the strength of association between independent and dependent variables. Results Results show that the estimated prevalence of PTSD was 254 (65.1%) and was higher among the females 191 (75.2%), those with no formal education 143 (56.3%), aged 40 years and above 121 (47.6%), and married 127 (50.0%). Results indicate that male respondents had a 51% reduced odds of developing PTSD burden compared to female respondents (AOR: 0.49; 95% CI: 0.30–0.81; P = 0.005). Individuals who did not use planning activities as a coping strategy had more than 2-fold increased odds of experiencing PTSD compared to those who planned activities (AOR: 2.43; 1.26–4.70; P = 0.008). Participants who did not have emotional support had close to 3-fold increased chances of developing PTSD compared to those who had emotional support (AOR: 2.94; 1.74–4.98; P ≤ 0.001). Participants who indicated they were not taking recourse to spirituality had more than 4-fold increased odds of experiencing PTSD compared to those who had spirituality (AOR: 4.40; 1.83–10.46; P = 0.001). Conclusion A considerable burden of PTSD among HIV clients attending health centre IVs in Lira District was notably higher and was associated with gender, planning activities, emotional support and spirituality. Early screening of PTSD among HIV clients is needed to alleviate the burden. There is also a need to include PTSD treatment services in the treatment programme of HIV care services in health centre IVs in Lira District.