Background Human immunodeficiency Virus (HIV) and consequently the acquired immune deficiency syndrome (AIDS) remain a significant public health problem, having claimed 36.3 million lives so far. In 2020, approximately 680,000 people died from AIDS-related illnesses worldwide. Despite increased access to antiretroviral treatment (ART), the burden of mortality and morbidity due to advanced HIV disease (AHD) has not significantly changed over the years. AHD individuals are more prone to opportunistic infections– including Mycobacterium tuberculosis (MTB) and Cryptococcal meningitis (CM). CM has been reported as a significant cause of mortality among people living with HIV (PLHIV), accounting for 15% of the global AIDS-related deaths in 2019. To keep track of the global commitments made by governments to end the AIDS epidemic as a public health threat by 2030, knowledge of the burden of AHD and its risk factors are essential. Methods A hospital-based cross-sectional study was conducted from February 2020 to February 2021. HIV-infected individuals on ART at the Buea Regional Hospital were screened for AHD using World Health Organization (WHO) consolidated guidelines. A pre-tested semi-structured questionnaire was administered to the consented participants, and blood, sputum, and urine samples were collected. Acid fast bacilli microscopy detection and TB culture were carried out following standard microbiological procedures. Cryptococcus antigen lateral flow tests were performed using sera. Chi-square and regression analysis were carried out on SPSS at a p < 0.05 significance level. Results From a total of 3,229 PLHIV adults on care in the study period, 327 (10.1%) were suspected of having AHD, and were enrolled in the study. Most of the enrolled individuals were women (62.4%) and the mean age of the participants was 40.5 ± 24.7 years. A total of 130 (39.8%, [95% CI, 34.41–45.29]) participants presented with AHD and 41 (35.7%, [95% CI, 26.94–45.12]) and 7 (6.7%, [95% CI, 2.72–13.25) had TB and Cryptococcal infections, respectively. AHD was associated with male gender (aOR; 3.9, 95% CI; 1.40–11.70), and being on ART for more than 12 months was protective (aOR; 0.1, 95% CI; 0.01–0.35). Conclusion Even when ART uptake has dramatically improved in Cameroon, AHD (35.7%) is far beyond the UNAIDS reduction target of 10% by 2020 and thus, improvement in the management of PLHIV is warranted.