BACKGROUND: Prior research has investigated various strategies to improve health, wellbeing and the job-related outcomes of nurses. However, the scope of this evidence is not clear and the types of intervention most likely to have positive outcomes are unknown. OBJECTIVE: To provide an overview and synthesis of the effectiveness of interventions conducted with the goal of improving health, wellbeing and the job-related outcomes of nurses. METHODS: A systematic database search was conducted from January 2000 to December 2018, with pre-defined criteria (Cochrane Central Register of Controlled Trials; MEDLINE and PubMed; EMBASE; CINAHL; PsycINFO; and BioMed Central). In total, 136 intervention studies with a total sample of 16,129 participants (range 9-3381) were included and evaluated. Data extraction, quality assessment and risk of bias analyses were performed. RESULTS: Studies included randomised controlled trials (RCTs; n = 52, 38%), randomised crossover design studies (n = 2, 1.5%) and non-randomised pre-post studies with a control group (n = 31, 23%) and without a control group (n = 51, 37.5%). The majority of interventions focused on education, physical activity, mindfulness, or relaxation. Thirty-seven (27%) studies had a multimodal intervention approach. On average, studies had relatively small samples (median = 61; mode = 30) and were conducted predominantly in North America (USA/Canada, n = 53). The findings were mixed overall, with some studies reporting benefits and others finding no effects. Dietary habits was the most successfully improved outcome (8/9), followed by indices of body composition (20/24), physical activity (PA) (11/14), and stress (49/66), with >70% of relevant studies in each of these categories reporting improvements. The lowest success rate was for work-related outcomes (16/32). Separate analysis of RCTs indicated that interventions that focus solely on education might be less likely to result in positive outcomes than interventions targeting behavioural change. CONCLUSIONS: Interventions targeting diet, body composition, PA, or stress are most likely to have positive outcomes for nurses' health and/or wellbeing. The methodologically strongest evidence (RCTs) is available for body composition and stress. Interventions relying solely on educational approaches are least likely to be effective. Organisational outcomes appear to be more challenging to change with lifestyle intervention, likely requiring more complex solutions including changes to the work environment. There is a need for more high-quality evidence since many studies had moderate or high risk of bias and low reporting quality.