Background: In countries where the majority of young children are enrolled in professional childcare, the childcare setting constitutes an important part of children’s caregiving environment. Research consistently shows that particularly the quality of the daily interactions and relationship between young children and their professional caregivers have long-term effects on a range of developmental child outcomes. Therefore, professional caregivers’ capacity for establishing high quality interactions with the children in their care is an important target of intervention. Methods: A prospective, parallel, cluster-randomized wait-list controlled trial is used to test the efficacy of the attachment- and mentalization theory informed Circle of Security (COS) approach adapted to the childcare setting (COS-Classroom) on caregiver interactive skills and mind-mindedness. Participants are professional caregivers of children aged 0–2.9 years working in center-based childcare in Denmark. Approximately 31 childcare centers, corresponding to an estimated 113 caregivers, are expected to participate. The primary outcome is caregiver Sensitive responsiveness measured with the Caregiver Interactive Profile Scales (CIP-scales). Secondary outcomes include caregiver Mind-mindedness, the five remaining CIP-scales (Respect for autonomy, Structure and limit setting, Verbal communication, Developmental stimulation, and Fostering positive peer interactions), and caregivers’ resources to cope with work-related stress. Data on structural factors (e.g., staff stability, caregiver-child ratio, and level of pre-service education), caregiver attachment style, acceptability and feasibility of the COS-C together with qualitative data on how the participants experience the COS-C is additionally collected to investigate moderating and confounding effects. Discussion: Examining the effectiveness of the COS-C in center-based childcare contributes to the knowledge of evidence-based intervention programs and can potentially improve the caregiver quality early childcare. Trial registration: ClinicalTrials.gov: NCT04654533. Prospectively registered December 4, 2020, https://clinicaltrials.gov/ct2/show/NCT04654533.