This retrospective study compared central line-associated bloodstream infection (CLABSI) rates per 1 000 central line days, and overall mortality before and during the COVID-19 pandemic in adult, paediatric, and neonatal ICU patients at King Abdul-Aziz Medical City-Riyadh who had a central line and were diagnosed with CLABSI according to the National Healthcare Safety Network standard definition. The study spanned between January 2018 and December 2019 (pre-pandemic), and January 2020 and December 2021 (pandemic). SARS-CoV-2 was confirmed by positive RT-PCR testing. The study included 156 CLABSI events and 46 406 central line days; 52 and 22 447 (respectively) in pre-pandemic, and 104 and 23 959 (respectively) during the pandemic. CLABSI rates increased by 2.02 per 1 000 central line days during the pandemic period (from 2.32 to 4.34, p < 0.001). Likewise, overall mortality rates increased by 0.86 per 1 000 patient days (from 0.93 to 1.79, p = 0.003). Both CLABSI rates (6.18 vs. 3.7, p = 0.006) and overall mortality (2.72 vs. 1.47, p = 0.014) were higher among COVID-19 patients compared to non-COVID-19 patients. The pandemic was associated with a substantial increase in CLABSI-associated morbidity and mortality.