We aimed to apply the Systems Engineering Initiative for Patient Safety (SEIPS) model to increase effectiveness and sustainability of the World Health Organization's (WHOs) hand hygiene (HH) guidelines within healthcare systems. Our cross-sectional, mixed-methods study took place at Jimma University Medical Center (JUMC), a tertiary care hospital in Jimma, Ethiopia, between November 2018 and August 2020 and consisted of three phases: baseline assessment, intervention, and follow-up assessment. We conducted questionnaires addressing HH knowledge and attitudes, interviews to identify HH barriers and facilitators within the SEIPS framework, and observations at the WHO's 5 moments of HH amongst healthcare workers (HCWs) at JUMC. We then implemented HH interventions based on WHO guidelines and results from our baseline assessment. Follow-up HH observations were conducted months later during the Covid-19 pandemic. 250 HCWs completed questionnaires with an average knowledge score of 61.4% and attitude scores indicating agreement that HH promotes patient safety. Interview participants cited multiple barriers to HH including shortages and location of HH materials, inadequate training, minimal Infection Prevention Control team presence, and high workload. We found an overall baseline HH compliance rate of 9.4% and a follow-up compliance rate of 72.1%. Drastically higher follow-up compared to baseline compliance rates were likely impacted by our HH interventions and Covid-19. HCWs showed motivation for patient safety despite low HH knowledge. Utilizing the SEIPS model helped identify institution-specific barriers that informed targeted interventions beyond WHO guidelines aimed at increasing effectiveness and sustainability of HH efforts.