Background COVID-19 experiences on noncommunicable diseases (NCDs) from district-level hospital settings during waves I and II are scarcely documented. The aim of this study is to investigate the NCDs associated with COVID-19 severity and mortality in a district-level hospital with a high HIV/TB burden. Methods This was a retrospective observational study that compared COVID-19 waves I and II at Khayelitsha District Hospital in Cape Town, South Africa. COVID-19 adult patients with a confirmed SARS-CoV-2 polymerase chain reaction (PCR) or positive antigen test were included. In order to compare the inter wave period, clinical and laboratory parameters on hospital admission of noncommunicable diseases, the Student t-test or Mann-Whitney U for continuous data and the X2 test or Fishers’ Exact test for categorical data were used. The role of the NCD subpopulation on COVID-19 mortality was determined using latent class analysis (LCA). Findings Among 560 patients admitted with COVID-19, patients admitted during wave II were significantly older than those admitted during wave I. The most prevalent comorbidity patterns were hypertension (87%), diabetes mellitus (65%), HIV/AIDS (30%), obesity (19%), Chronic Kidney Disease (CKD) (13%), Congestive Cardiac Failure (CCF) (8.8%), Chronic Obstructive Pulmonary Disease (COPD) (3%), cerebrovascular accidents (CVA)/stroke (3%), with similar prevalence in both waves except HIV status [(23% vs 34% waves II and I, respectively), p = 0.022], obesity [(52% vs 2.5%, waves II and I, respectively), p textless0.001], previous stroke [(1% vs 4.1%, waves II and I, respectively), p = 0.046]. In terms of clinical and laboratory findings, our study found that wave I patients had higher haemoglobin and HIV viral loads. Wave II, on the other hand, had statistically significant higher chest radiography abnormalities, fraction of inspired oxygen (FiO2), and uraemia. The adjusted odds ratio for death vs discharge between waves I and II was similar (0.94, 95%CI: 0.84-1.05). Wave I had a longer average survival time (8.0 vs 6.1 days) and a shorter average length of stay among patients discharged alive (9.2 vs 10.7 days). LCA revealed that the cardiovascular phenotype had the highest mortality, followed by diabetes and CKD phenotypes. Only Diabetes and hypertension phenotypes had the lowest mortality. Conclusion Even though clinical and laboratory characteristics differed significantly between the two waves, mortality remained constant. According to LCA, the cardiovascular, diabetes, and CKD phenotypes had the highest death probability.