Background: Family caregivers of children with chronic health conditions experience substantial physical and mental health burdens, including burnout, anxiety, depression, fatigue, and sleep disturbances. Despite this need, validated digital mental health tools tailored to family caregivers remain limited. AI-powered conversational agents offer a promising approach for delivering on-demand, personalized mental health support, yet development and evaluation frameworks for this population are lacking. Objective: This paper describes the iterative development and formative evaluation of COCO (Caring of Caregivers Online), a conversational agent designed for family caregivers of children with chronic health conditions. COCO integrates problem-solving therapy (PST) and motivational interviewing (MI) within a human-in-the-loop development framework that progressed from rule-based interactions to a large language model (LLM)–powered conversational agent. Methods: COCO was developed across four phases: (1) caregiver persona and dialogue development based on PST and MI; (2) usability testing of a low-fidelity prototype with standardized patients in a single session of PST; (3) usability testing of a high-fidelity prototype with caregivers in a single session of PST (n=38); (4) integration of an LLM into COCO. The Wizard-of-Oz method was used across phases 2 and 3 to collect naturalistic dialogues and refine COCO’s conversational design. In phase 3, usability of COCO was assessed using the System Usability Scale (SUS). Caregiver emotions were measured before and after the session using 6 subscales of the PANAS-X. In phase 4, GPT-4 was integrated into COCO with few-shot learning and evaluated by research team members using the caregiver personas. Descriptive statistics were used to summarize quantitative measures. The MI principles and techniques used by COCO across the 4 phases were coded using the . Results: In phase 1, 4 gold-standard dialogues were developed using caregiver personas. In phase 2, standardized patients described COCO as validating and identified its problem-solving and on-demand support as helpful for caregivers. In phase 3, COCO-Wizard-of-Oz achieved a mean SUS score of 75.6% (SD 12.9%), reflecting acceptable usability. Participants demonstrated significant improvement in negative affect, sadness, guilt, and fatigue following PST sessions (