On 10 April 1963, Thresher sank during deep-diving tests about 350 km (220 mi) east of Cape Cod, Massachusetts, killing all 129 crew and shipyard personnel aboard.

She also had the most advanced weapons system, including launchers for the U.S. Navy's newest anti-submarine missile, the SUBROC, as well as passive and active sonar that could detect vessels at unprecedented range.

Naval Institute's monthly journal Proceedings that "the Navy had depended upon this performance to the extent that it had asked for and received authority to build 14 of these ships, as well as an additional 11 submarines with very much the same characteristics.

This was the first time since World War II that we had considered our design sufficiently advanced to embark upon construction of a large class of general-purpose attack submarines.

[6] On 18 October 1961, Thresher, in company with the diesel-electric submarine Cavalla, headed south on a three-week test and training cruise to San Juan, Puerto Rico, arriving 2 November.

Since no shore power connection was available in San Juan, the ship's backup diesel generator was used to carry the "hotel" electrical loads.

The crew eventually borrowed cables from another ship in the harbor and connected them to the adjacent Cavalla, which started her diesels and provided enough power to allow Thresher to restart her reactor.

In March, she participated in NUSUBEX 2–62 (an exercise designed to improve the tactical capabilities of nuclear submarines) and in anti-submarine warfare training with Task Group ALPHA.

After repairs at Groton, Connecticut, by the Electric Boat Company, Thresher went south for more tests and trials off Key West, Florida, then returned northward.

The submarine entered Portsmouth Shipyard on 16 July 1962 to begin a scheduled six-month post-shakedown availability to examine systems and make repairs and corrections as necessary.

Following standard practice, Thresher slowly dove deeper as she traveled in circles under Skylark – to remain within communications distance – pausing every 100 ft (30 m) of depth to check the integrity of all systems.

President John F. Kennedy ordered all flags to be flown at half staff from 12 to 15 April in honor of the 129 lost submariners and shipyard personnel.

The Navy quickly mounted an extensive search with surface ships and support from the Naval Research Laboratory (NRL), with its deep-search capability.

The NRL deep-towed camera system and personnel later operated from James M. Gilliss with some success, finding debris later confirmed to be from Thresher.

Before her departure from NRL in Washington, Mizar was equipped with highly sensitive proton magnetometers furnished by the instrument division of Varian Associates in Palo Alto.

[24]: 41 Deep-sea photography, recovered artifacts, and an evaluation of Thresher's design and operational history permitted a court of inquiry to conclude that the submarine had probably suffered the failure of a salt-water piping system joint that relied heavily on silver brazing instead of welding.

[29] At the time, reactor-plant operating procedures did not allow for a rapid reactor restart following a scram, or even the ability to use steam remaining in the secondary system to propel the submarine to the surface.

Reflecting on the situation in later life, McCoole was sure that he would have delayed shutting the valves, thus allowing the boat to "answer bells" and drive itself to the surface, despite the flooding in the engineering spaces.

Admiral Rickover noted that the procedures were for normal operating conditions, and not intended to restrict necessary actions in an emergency involving the safety of the ship.

After the accident Rickover further reduced plant restart times, which had already been gradually improving with new technology and operating experience, in addition to limiting factors that could cause a shutdown.

These reports provide results of the environmental sampling of sediment, water, and marine life, which is performed to ascertain whether Thresher's nuclear reactor has had a significant effect on the deep-ocean environment.

Ballard's robotic survey showed that the depth at which Thresher had sunk caused implosion and total destruction; the only recoverable piece was a foot of mangled pipe.

In February 2020, in response to a FOIA lawsuit by military historian James Bryant, a federal court ordered the Navy to begin releasing documents by May 2020.

[39] Following the release of the July 18, 2020, court-mandated report, the Navy stated that they had identified and approved additional resources and reservists to begin processing the documents in August.

[45]On 8 April 2013, Bruce Rule, US Office of Naval Intelligence lead acoustic analyst for over 42 years, published his own analysis of the data collected by USS Skylark and Atlantic SOSUS arrays in a paper in the Navy Times.

[46][47] Rule based his analysis on SOSUS data that was highly classified in 1963, was not discussed in open session of the Court of Inquiry and was not revealed at the congressional hearings.

According to Rule, SOSUS data indicates that after two minutes of electrical instability, the bus failed at 09:11 a.m., causing the main coolant pumps to trip off.

Rule's analysis holds that flooding (whether from a silver brazed joint or anywhere else) played no role in the reactor scram or the sinking, and that Thresher was intact until she imploded.

[46] When the Court of Inquiry delivered its final report, it recommended that the Navy implement a more rigorous program of design review and safety inspections during construction.