Hospital-acquired infections (HAIs) are a critical challenge in intensive care units (ICUs), contributing to significant morbidity, mortality, and healthcare costs. This retrospective cross-sectional study evaluated the prevalence, types, and risk factors for HAIs among 113 ICU patients at Nelson Mandela Academic Hospital, Mthatha, South Africa, admitted between January 2020 and December 2022. Patients included were hospitalized for more than 48 hours. Data analyzed encompassed demographics, ICU stay duration, HAI types, microorganisms, invasive device use, comorbidities, and outcomes. The cohort's median age was 33 years, with 61.1% having chronic illnesses. The ICU mortality rate was 26.5%. All patients had urinary catheters, and 53.1% used multiple invasive devices, including mechanical ventilation and central lines. Catheter-associated urinary tract infection (CAUTI) was the most common HAI, followed by surgical site infection, ventilator-associated pneumonia, and central line-associated bloodstream infection. The Acinetobacter baumannii complex was the predominant pathogen. Logistic regression revealed intravenous central lines as a significant risk factor for HAIs, with CAUTI strongly linked to ICU mortality (p < 0.001). These findings highlight the urgent need for targeted infection prevention strategies, focusing on invasive medical device management to reduce HAI prevalence and associated mortality in ICU settings.