Blood cultures (BCs) remain a key investigation in ED patients at risk of bacteraemia. The aim of this study was to assess the effect of a multi-modal, nursing-led intervention to improve the quality of BCs in the ED, in terms of single culture, underfilling and contamination rates. The present study was conducted in the ED of a large urban tertiary referral hospital. The study included four phases: pre-intervention, intervention, post-intervention and sustainability periods. A multi-modal intervention to improve BC quality consisting small group education, posters, brief educational videos, social media presence, quality feedback, small group/individual mentoring and availability of BC collection kits was designed and delivered by two senior ED nurses over 7 weeks. Study data comprised rates of single, underfilled and contaminated cultures in each of three 18-week periods: pre-intervention (baseline), post-intervention and sustainability. Over the study period 4908 BC sets were collected during 2347 episodes of care in the ED. Single culture sets reduced from 56.2% in the pre-intervention period to 22.8% post-intervention (P < 0.01) and 18.8% in the sustainability period (P < 0.01). Underfilled bottle rates were also significantly reduced (aerobic 52.8% pre-intervention to 19.2% post-intervention, 18.8% sustainability, anaerobic 46.8% pre-intervention to 23.3% post-intervention, 23.8% sustainability). Skin contaminants were grown from 3.7% of BC sets in the pre-intervention period, improving to 1.5% in the post-intervention period (P < 0.001) and 2.1% in the sustainability period (P = 0.03). Total volume of blood cultured was significantly associated with diagnosis of bacteraemia. Significant improvements in BC quality are possible with nursing-based interventions in the ED.