Antimicrobial resistance (AMR) is a pressing global health challenge, with sub-Saharan Africa experiencing the highest burden of AMR-related deaths. Inappropriate prescribing and rising antibiotic consumption drive AMR, while limited local data hampers antimicrobial stewardship efforts. This study analysed Global Point Prevalence Survey of Antimicrobial Consumption and Resistance (Global-PPS) data from Tygerberg Hospital to identify antimicrobial use trends and inform stewardship priorities. Standard Global-PPS methodology was employed at three distinct time points. All inpatients prescribed at least one antimicrobial on the day of each survey were included in the analysis. Among 3,524 hospitalized patients, 25.9% (911/3,524) received antimicrobial therapy. Overall antimicrobial use decreased significantly (p < 0.05), with the largest reduction among paediatric patients (p < 0.01). Community-acquired infections accounted for the majority of prescriptions (50.7%; 483/952) and empirical antibiotic use was high (85.3%, 872/1022). ‘Access’ antibiotics constituted 62.7% (750/1196) of prescriptions. Single-dose prescriptions for surgical prophylaxis accounted for 17.6% (15/85). This study demonstrates progress in stewardship, particularly among paediatric inpatients. Ongoing monitoring of broad-spectrum antibiotic use and adherence to single-dose surgical prophylaxis guidelines are essential priorities. Continued Global-PPS surveillance is crucial to track trends and guide future AMS interventions.