Though Splenda and Stevia are both considered zero-calorie sweeteners, and so share some similarities, there are a number of differences in the two. Typically, when people speak of "Stevia," they mean Stevia Rebaudiana, a Central and South American herb, the leaves of which have been used for centuries as a sweetener. Splenda, on the other hand, is a manufactured product, the main ingredient of which (sucralose) is the result of a chemical process where pairs of oxygen and hydrogen atoms in sugar are replaced with chlorine atoms.
Both Splenda and Stevia are sweeter than sugar. Stevia extracts are 200 - 300x sweeter than sugar, while Splenda is about 600x sweeter. Both are stable at high temperatures, meaning that they can be used in the place of sugar when cooking or baking. Though Stevia itself is a natural product, both Coke and Pepsi manufacture derivatives of it -- Truvia and Purevia, respectively -- that compete with Splenda in the artificial sweetener marketplace. They come in individual packets, just like Splenda.
Though both are marketed as "zero-calorie," only Stevia, or at least its derivatives, appears to actually be "zero-calorie." While the sucralose in Splenda is not absorbed by the body and is therefore free of calories, Splenda itself is not pure sucralose. Before packages of Splenda leave the factory, dextrose or maltodextrin, both of which contain calories, are added for bulk. Thanks to those extra ingredients, an individual packet of Splenda delivers about three calories along with the sweet taste. A comparable packet of Truvia does contain carbohydrates, from the indigestible sugar alcohol Erythritol, but no calories.
The GRAS List
The most important differences between Stevia and Splenda are related. The first, and most important difference is that Splenda is officially approved for use as a sweetener by the Food and Drug Administration, and is present on that organization's GRAS (Generally Recognized As Safe) list, along with Nutrasweet and saccharin. Stevia itself is not approved by the FDA for use as a sweetener, is not on the GRAS list, and is only allowed to be imported into the United States as a food supplement. Indeed, the FDA specifically condemns the use of Stevia as a sweetener, saying that as such, Stevia "is considered an unsafe food additive." Technically, this is not because the FDA knows that Stevia is unsafe when used as a sweetener, but rather because there are no scientific studies showing that Stevia is safe. Splenda makes the GRAS list because in the FDA's estimation, it has been proven safe. The FDA does take a slightly different view of Coke and Pepsi's Stevia derivatives. While neither make the GRAS list, the FDA officially "declined to object" when those companies informed the organization that they would begin using Truvia and Purevia in their products.
Perhaps unsurprisingly, the natural foods industry takes an almost exact opposite view of each product, embracing Stevia as natural, and condemning Splenda and sucralose for a host of supposed health effects. Truvia and Purevia provoke a more schizophrenic response, as they are manufactured, but at least derived from Stevia.