Challenges calling for integrated approaches to health, such as the One Health (OH) approach, typically arise from the intertwined spheres of humans and animals, and the ecosystems constituting their environment. Initiatives addressing such wicked problems commonly consist of complex structures and dynamics. The Network for Evaluation of One Health (NEOH) proposes an evaluation framework anchored in systems theory to address the intrinsic complexity of OH initiatives and regards them as subsystems of the context within which they operate. Typically, they intend to influence a system with a view to improve human, animal, and environmental health. The NEOH evaluation framework consists of four overarching elements, namely: (1) the definition of the OH initiative and its context; (2) the description of its theory of change with an assessment of expected and unexpected outcomes; (3) the process evaluation of operational and supporting infrastructures (the 'OHness'); and (4) an assessment of the association(s) between the process evaluation and the outcomes produced. It relies on a mixed-methods approach by combining a descriptive and qualitative assessment with a semi-quantitative scoring for the evaluation of the degree and structural balance of 'OH-ness' (summarised in an OH-index and OH-ratio, respectively) and conventional metrics for different outcomes in a multi-criteria-decision analysis. We provide the methodology for all elements, including ready-to-use Microsoft Excel spread-sheets for the assessment of the 'OH-ness' (Element 3) and further helpful worksheets as electronic supplements. Element 4 connects the results from the assessment of the 'OH-ness' to the methods and metrics described in Chapters 4 to 6 in this handbook. Finally, we offer some guidance on how to produce recommendations based on the results. The presented approach helps researchers, practitioners, policy makers and evaluators to conceptualise and conduct evaluations of integrated approaches