Background: We aimed to evaluate the prevalence of burnout among French general practitioners in private practice and to study the risk and protective factors of burnout. Methods: A nationwide cross-sectional study was conducted with French GPs working in a private practice in France who were asked to fulfil an internet questionnaire. We used the secure internet application REDCap®. Exclusion criteria were only working in a hospital, substitute doctors, and internship students. There was a putative sample size of 88,886 GPs. We retrieved the Maslach Burnout Inventory (MBI), occupational characteristics (type of installation, emergency regulated shifts, night shifts, university supervisor, weekly hours worked, seniority), and personal characteristics such as age, gender, marital status, and number of children. Results: We included 1926 GPs among the 2602 retrieved questionnaires. A total of 44.8% of French liberal GPs were experiencing burnout, with 4.8% (95%CI 3.9–5.9%) experiencing severe burnout. The risk factors of severe burnout were male gender (RR = 1.91, 95%CI 1.15–3.16), working in a suburban area (5.23, 2.18–12.58), and having more than 28 appointments per day (1.95, 1.19–3.19). Working more than 50 h weekly showed a tendency to increase the risk of severe burnout (1.55, 0.93–2.59, p = 0.095), with a significant increase in the risk of low and moderate burnout (1.31, 1.02–1.67 and 1.86, 1.34–2.57, respectively). Protective factors were mainly resident training, which decreased the risk of both low, moderate, and severe burnout (0.65, 0.51–0.83; 0.66, 0.48–0.92; and 0.42, 95%CI 0.23–0.76, respectively). Performing home visits decreased the risk of severe burnout (0.25, 0.13–0.47), as did group practice for intermediate level of burnout (0.71, 0.51–0.96). Conclusion: GPs are at a high risk of burnout, with nearly half of them in burnout, with burnout predominantly affecting males and those between the ages of 50 and 60 years old. The main risk factors were a high workload with more than 28 appointments per day or 50 h of work per week, and the main protective factors were related to social cohesion such having a teaching role and working in a group practice with back-office support.