Objective: Diabetes is a defining disease of the 21st century because of its rising prevalence, association with obesity, and enormous health impact. Abundant evidence shows that lifestyle interventions can delay or prevent type 2 diabetes (T2D) in adults, offer relief, and sometimes achieve complete remission. Despite this empowering message, there are no clinical practice guidelines that focus primarily on lifestyle interventions as first-line management of prediabetes and T2D. Our objective, therefore, is to offer pragmatic, trustworthy, and evidence-based guidance for clinicians in using the 6 pillars of lifestyle medicine—nutrition, physical activity, stress management, sleep, social connectedness, avoidance of risky substances—for managing adults with T2D and in preventing T2D in adults with prediabetes or a history of gestational diabetes mellitus. Methods: We used well-established, peer-reviewed guideline methodology to develop evidence-based key action statements (recommendations) that facilitate quality improvement in clinical practice. The guideline development group included 20 members representing consumers, advanced practice nursing, cardiology, clinical pharmacology, behavioral medicine, endocrinology, family medicine, lifestyle medicine, nutrition and dietetics, health education, health and wellness coaching, sleep medicine, sports medicine, and obesity medicine. Recommendation strength was based on the aggregate evidence supporting a key action statement plus a comparison of associated benefits vs harms/costs. Multiple literature searches, conducted by an information specialist, identified 8 relevant guidelines, 118 relevant systematic reviews, and 112 randomized clinical trials. The guideline underwent extensive internal, external, and public review and comment prior to publication. Results: We developed 14 key action statements and associated evidence profiles, each with a distinct quality improvement goal in the context of lifestyle interventions for T2D. Strong recommendations were made regarding advocacy for lifestyle interventions; assessing baseline lifestyle habits; establishing priorities for lifestyle change; prescribing aerobic and muscle strength physical activity; reducing sedentary time; identifying sleep disorders; prescribing nutrition plans for prevention and treatment; promoting peer/familial support and social connections; counseling regarding tobacco, alcohol, and recreational drugs, and establishing a plan for continuity of care. Recommendations were made regarding identifying the need for psychological interventions and for adjusting (deprescribing) pharmacologic therapy. We include numerous tables and figures to facilitate implementation, a plain-language summary for consumers, and an executive summary for clinicians as separate publications. Conclusions: There is robust research evidence supporting the efficacy of lifestyle interventions in preventing, treating, and achieving remission of T2D in adults. Our multidisciplinary guideline development group successfully synthesized this evidence into 14 key action statements that can be used by clinicians and other healthcare professionals to improve quality of care for adults with, or at-risk for, T2D. Despite the research gaps and implementation challenges we highlight in the guideline we believe strongly that our recommendations have immediate relevance and can help raise awareness and shift the paradigm of T2D management towards optimal use of lifestyle interventions.