Background <p>Clinical uncertainty is an inherent component of primary care practice. Family physicians frequently face diagnostic ambiguity, time pressure, and limited access to diagnostic resources, which may affect decision-making and patient outcomes. However, evidence on how family physicians in Türkiye manage diagnostic uncertainty remains limited.</p> Methods <p>This mixed-methods study included 20 family physicians practicing in primary care settings in Türkiye. Quantitative data were collected using the Physicians’ Reactions to Uncertainty Scale (PRUS) and the Melbourne Decision-Making Questionnaire I-II (MDMQ). Semi-structured interviews were then conducted and analyzed thematically using the Braun and Clarke framework.</p> Results <p>Quantitative findings showed moderate-to-high emotional reactions to uncertainty and variation in decision-making styles among participants. Thematic analysis of the interviews revealed six key themes: diagnostic challenges and systemic barriers as major sources of uncertainty; specialist consultation, peer support, and patient communication as the main coping strategies; and the significant influence of patient compliance, physicians’ experience, and time pressure on decision-making. High patient load, referral difficulties, and inadequate digital systems were identified as major health system challenges. Physicians consistently emphasized the importance of case-based training and professional development, while also highlighting the role of transparent physician–patient communication in reducing uncertainty.</p> Conclusions <p>Diagnostic uncertainty is a multifaceted challenge in primary care in Türkiye, influenced by individual, systemic, and patient-related factors. Strengthening case-based educational programs, improving referral processes, and reducing patient load may enhance physicians’ ability to manage uncertainty and improve patient outcomes.</p> Clinical trial number <p>Not applicable.</p>