Navy carrier strike groups led by the USS Stennis and USS Eisenhower will represent the main American naval force during the exercise, according to service spokesman Lt. Cmdr John Fage.
Naval forces from other U.S. allies, including the United Kingdom, France, Saudi Arabia and United Arab Emirates, are expected to have a sizable presence during the multilateral exercise.
Command elements from NATO will also participate in coordination and execution on certain portions of the wargame, according to recent reports.
The exercise is scheduled to wrap up on Sept. 27, to coincide with President Obama's visit with Israeli Prime Minister Benjamin Netanyahu in Washington, reports state.
The massive naval combat drill comes at a particularly difficult time for both Washington and Tehran.
In March, Iranian military leaders announced the country would begin arming its warships patrolling the Straits with short-range missiles.
With an effective range of between 200 to 300km, those missiles would be able to strike targets from Straits of Hormuz to the Sea of Oman from the Iranian coastline, Tehran claimed at the time.
U.S. Navy commanders have also beefed up their Persian Gulf fleet, to defend against any potential Iranian attack.
The Navy is doubling the number of its mine-hunting ships patrolling the key waterway. In the past, the Iranian navy has peppered its coastal waters with sea-based mines as a way to protect its shores from attack.
Navy leaders have also outfitted the destroyers and cruisers in the region with powerful Gatling guns. The weapons are ideal for taking out the small, fast-moving patrol boats the Iranian navy commonly uses to patrol the strait.
The ongoing diplomatic battle playing out between Iran, the United States and its allies over the country's nuclear enrichment program has also raised tensions in the region and provided a stark backdrop for the upcoming Navy drill.
Iran maintains the work is geared toward specifically peaceful means. However, American military and intelligence officials remain convinced Tehran is establishing the groundwork to construct an atomic bomb.
In recent weeks, Jerusalem has been indicating it's preparing to launch a preemptive military attack against Iranian nuclear sites.
Netanyahu has said repeatedly that Israel will not hesitate to launch a preemptive attack against Iran's nuclear facilities if it becomes clear Iran is pursuing nuclear weapons.
That push has strained U.S.-Israeli relations, given the White House's strategy of resolving the issue via diplomatic means.
But in a new report issued Thursday, a slew of national security experts argued that any strike against Iran would lead to a protracted conflict that would have severe ramifications to the entire region.
The report, backed by over 30 defense experts, claim such a strike would not eliminate Iran's nuclear program but only delay the country's efforts by four years.