Background: Pressure injuries are a ubiquitous, yet largely preventable, hospital acquired complication commonly seen in critically ill patients in the intensive care unit. Objectives: The objectives of this study were to implement targeted evidence-based pressure injury prevention strategies and evaluate their effect through measurement of patient pressure injury observations. Methods: A prospective multiphased design was used in the intensive care unit of an Australian tertiary referral hospital using three study periods (period 1, weeks 1–18; period 2, weeks 19–28; and period 3, weeks 29–52). The interventions included staff-focused interventions and patient-focused interventions, with the latter defined in a work unit guideline. Weekly visual observations of critically ill patients' skin integrity were conducted by trained research nurses over 52 weeks from November 2015 to November 2016. The primary outcome measure was a pressure injury of any stage, identified at the weekly observation, and the effect of the intervention was evaluated through logistic regression. Reporting rigour has been demonstrated using the Standards for Quality Improvement Reporting Excellence checklist. Results: Over the whole study, 15.4% (95% confidence interval [CI] = 12.6, 18.2%, 97/631) of patients developed a pressure injury, with the majority of these injuries (73.2%, 95% CI = 64.4%, 82.0%, 71/97) caused by medical devices. After adjustment for covariates known to influence hospital-acquired pressure injury development, pressure injury rates for period 3 compared with period 1 were reduced (odds ratio = 0.41, 95% CI = 0.20–0.97, p = 0.0126). Conclusions: We found the use of defined pressure injury prevention strategies targeted at both staff and patients reduced pressure injury prevalence.