Sweeteners are food additives used in processed foods and beverages, as well as health products and medicines. Due to low cost, zero calories, and intense sweetness, nonnutritive sweeteners have been widely used to replace table sugar and become the preferred strategy to manage human health. Non-nutritive sweeteners are traditionally considered to be metabolically inert, while more and more evidence indicates that they affect human health by perturbing gut microbiota and energy homeostasis. The impact of non-nutritive sweeteners on metabolic diseases still remains controversial. This review covered a total of 10 commonly used non-nutritive sweeteners, either naturally occurring or artificial, and summarized their origin, applications, and impacts on metabolic diseases, especially obesity, diabetes, and nonalcoholic fatty liver disease. The sensory assessment methods were summarized and applied to evaluate the suitability and consumer acceptance of sweeteners. The purpose of this review is to summarize the potential impacts of sweeteners on metabolic diseases, guide the safe application of sweeteners, and speculate on the future development of sweeteners.