Background Coagulase-negative staphylococci (CoNS) are increasingly becoming emerging bacteria of ‘true’ clinical significance in hospital setting. We investigated an unusual rise in incidence of CoNS bacteraemia among in-patients in a private tertiary hospital, Southwest Nigeria and described ways of mitigation. Methods A descriptive epidemiology of all cases of CoNS bacteraemia reported among in-patients between April 2022 and June 2022 was conducted. Blood cultures were processed in an automated system. Phenotypic and molecular analyses of CoNS were done according to established guidelines. A multimodal infection prevention and control (IPC) approach by the World Health Organisation was implemented. Findings A total of 82 blood cultures (non-duplicate samples) were requested during the period. Of these, 30 (36.5%) were culture-positive and 10 of the isolates were CoNS (10/30, 33.3%). Cumulative incidence of CoNS bacteraemia was 12 cases per 100 patients over 90days from 1–2% in previous months. Staphylococcus haemolyticus (4/10, 40%), Staphylococcus hominis (3/10, 30%), Staphylococcus epidermidis (2/10, 20%) and Staphylococcus saccharolyticus (1/10, 10%) were identified. All isolates were resistant to ciprofloxacin, Trimethoprim-sulfamethoxazole and cefoxitin (methicillin-resistant) while they were all susceptible to both Vancomycin and linezolid. All the isolates fell into S. epidermidis and S. haemolyticus cluster groups. The rates reduced to baseline on the implementation of the IPC strategies. Conclusion The unusual rise of CoNS incidence in the hospital was caused by multi-drug resistant cluster groups of S. haemolyticus and S. epidermidis which was curtailed by the implementation of multimodal strategies.