Maintaining healthy body weight is an important component of any effective diabetes management plan. However, glycemic management using insulin generally leads to weight gain. In addition, weight loss medications prescribed for diabetes management are often associated with adverse side effects, which limit their long-term usage. Alternatively, nutrition intervention provides a safe, readily accessible, and inexpensive option for diabetes management. This study describes a composition of phytonutrients comprising berberine, cinnamaldehyde, and curcumin for glycemic and weight management. Functional complementarity between berberine, cinnamaldehyde, and curcumin provides an effective means to improve insulin sensitivity without increasing adiposity. In primary human omental preadipocytes, cinnamaldehyde and curcumin additively enhance insulin-stimulated activation of Akt2 and glucose uptake, whereas berberine inhibits de novo fatty acid biosynthesis and fat cell differentiation. In a diet-induced obesity murine model, a dietary supplement with berberine, cinnamaldehyde, and curcumin prevents weight gain, improves glucose tolerance, and reduces HbA1c, blood lipids, visceral adiposity, and liver steatosis. Collectively, the composition of phytonutrients comprising berberine, cinnamaldehyde, and curcumin protects against obesity and pre-diabetic conditions in a diet-induced obesity murine model. Safety and efficacy assessment of nutrition intervention using combined berberine, cinnamaldehyde, and curcumin for glycemic and weight management in future clinical trials are warranted.