Older people living in care homes are at risk from avoidable harms, which may require hospital attendance or admission. This paper describes a mixed methods evaluation of a large quality improvement (QI) programme that provides skills training and facilitated support to staff in 29 care homes across two localities in the West Midlands, UK. The Safety Attitudes Questionnaire (SAQ) is used to assess changes to care home safety climate between baseline and programme end at 24 months. We use routinely collected data to assess pre- and post-programme avoidable harms and hospital attendance/admission rates. Semi-structured interviews with programme managers (n = 18), and staff (n = 49) in four case study homes are also used to assess perspectives on programme implementation. Our results show that safety climate scores increase by 1.4 points. There are significant reductions in falls (p = 0.0006), severe pressure ulcers (p = 0.014), UTIs (p = 0.001) and ‘any’ events (p = 0.0003). Emergency hospital attendances reduced, but admissions increased. Interview participants report improvements to teamwork, working practices, information sharing, knowledge and skills. Upskilling care home staff can improve working practices and attitudes towards resident safety and care quality, which may be associated with significant reductions in avoidable harms rates. Care staff turnover rates are high, which may impact the potential for longer-term sustainability of the changes observed.