OBJECTIVE To examine open-flame and/or high-temperature cooking (grilling/barbecuing, broiling, or roasting) and doneness preferences (rare, medium, or well done) for red meat, chicken, and fish in relation to type 2 diabetes (T2D) risk among U.S. adults who consumed animal flesh regularly (≥2 servings/week). RESEARCH DESIGN AND METHODS The prospective studies included 52,752 women from the Nurses’ Health Study (NHS) (followed during 1996–2012), 60,809 women from NHS II (followed during 2001–2013), and 24,679 men from the Health Professionals Follow-Up Study (HPFS) (followed during 1996–2012) who were free of diabetes, cardiovascular disease, and cancer at baseline. Incident cases of T2D were confirmed by validated supplementary questionnaires. RESULTS We documented 7,895 incident cases of T2D during 1.74 million person-years of follow-up. After multivariate adjustments including baseline BMI and total consumption of red meat, chicken, and fish, higher frequency of open-flame and/or high-temperature cooking was independently associated with an elevated T2D risk. When comparing open-flame and/or high-temperature cooking >15 times/month with <4 times/month, the pooled hazard ratio (HR) (95% CI) of T2D was 1.28 (1.18, 1.39; Ptrend <0.001). When comparing the extreme quartiles of doneness-weighted frequency of high-temperature cooking, the pooled HR (95% CI) of T2D was 1.20 (1.12, 1.28; Ptrend <0.001). These associations remained significant when red meat and chicken were examined separately. In addition, estimated intake of heterocyclic aromatic amines was also associated with an increased T2D risk. CONCLUSIONS Independent of consumption amount, open-flame and/or high-temperature cooking for both red meat and chicken is associated with an increased T2D risk among adults who consume animal flesh regularly.