The cluster randomized trial ARena (Sustainable reduction of antibiotic-induced antimicrobial resistance, 2017-2020) promoted the appropriate use of antibiotics for acute non-complicated infections in primary care networks (PCNs) in Germany. A process evaluation aimed to provide insights into determinants of practice and explored factors associated with antibiotic prescribing patterns. In a nested mixed-methods approach, a three-waves survey used study-specific questionnaires for participating physicians and medical assistants to assess potential impacts and uptake of the complex intervention program. Stakeholders received a one-time online questionnaire to reflect on network-related aspects. Semi-structured, open-ended interviews with a purposive sample of physicians, medical assistants and stakeholders explored aspects regarding the acceptance of the program components for daily practice and the perceived sustainability of intervention component effects. The intervention components were perceived to be smoothly integrable into practice routines. The highest uptake was reported for the educational components: feedback reports, background information, e-learning modules, and disease specific quality circles. Participation in PCNs was seen as motivational factor for guideline-oriented patient care and the adoption of new routines Future approaches to fostering appropriate use of antibiotics by targeting health literacy competencies and clinician’s therapy decisions should combine evidence-based information sources, audit and feedback reports and QCs.