For those looking for an answer specific to the United States, it’d be the Chesapeake Bay. This estuary covers 64,000 square miles. However, the largest estuary in the world is in Canada. This is the Gulf of the Saint Lawrence River. Out of the ten Canadian provinces, half of them border this estuary. Compared to five out of fifty states, yeah, that’s bigger in every measure of the word “bigger.”
Many sources note that the Gulf of the Saint Lawrence River covers 390,000 square miles. In every aspect, it beats out the Chesapeake Bay for largest estuary in the world. Since this isn’t going to change anytime soon or relatively quickly, it’s likely to stay the world’s largest estuary.
Water constantly flows in and out of an estuary, salt water from sea, fresh water from a river head, so this isn't a once and for all conclusion.
Many have given as the largest Chesapeake Bay, a watershed covering 64,000 square miles and covering parts of six different states of the USA but the estuary of the St Lawrence river in Canada is larger.