When the aircraft arrived from London earlier that morning, the previous flight crew had reported a frozen door seal and abnormal noises coming from the right aft service door. They requested a full inspection of the door. The inspection was carried out by a ground engineer who then performed a pressurization leak check. In order to carry out this check without requiring the aircraft's engines, the pressurization system was set to "manual". However, the engineer failed to reset it to "auto" on completion of the test.
After the aircraft was returned into service, the flight crew overlooked the pressurisation system state on three separate occasions: during the pre-flight procedure, the after-start check, and the after take-off check. During these checks, no one in the flight crew noticed the incorrect setting. The aircraft took off at 9:07 with the pressurization system still set to "manual", and the aft outflow valve partially open.
As the aircraft climbed, the pressure inside the cabin gradually decreased. As it passed through an altitude of 12,040 feet (3,670 m), the cabin altitude warning horn sounded. The warning should have prompted the crew to stop climbing, but it was misidentified by the crew as a take-off configuration warning, which signals that the aircraft is not ready for take-off, and can only sound on the ground.
In the next few minutes, several warning lights on the overhead panel in the cockpit illuminated. One or both of the equipment cooling warning lights came on to indicate low airflow through the cooling fans (a result of the decreased air density), accompanied by the master caution light. The passenger oxygen light illuminated when, at an altitude of approximately 18,000 feet (5,500 m), the oxygen masks in the passenger cabin automatically deployed.
Shortly after the cabin altitude warning sounded, the captain radioed the Helios operations centre and reported "the take-off configuration warning on" and "cooling equipment normal and alternate off line". He then spoke to the ground engineer and repeatedly stated that the "cooling ventilation fan lights were off". The engineer (the one who had conducted the pressurization leak check) asked "Can you confirm that the pressurization panel is set to AUTO?" However, the captain, already experiencing the onset of hypoxia's initial symptoms, disregarded the question and instead asked in reply, "Where are my equipment cooling circuit breakers?". This was the last communication with the aircraft.
The aircraft continued to climb until it leveled off at FL340, approximately 34,000 feet (10,000 m). Between 09:30 and 09:40, Nicosia ATC repeatedly attempted to contact the aircraft, without success. At 09:37, the aircraft passed from Cyprus Flight Information Region (FIR) into Athens FIR, without making contact with Athens ATC. Nineteen attempts to contact the aircraft between 10:12 and 10:50 also met with no response, and at 10:40 the aircraft entered the holding pattern for Athens Airport, at the KEA VHF omnidirectional range, still at FL340. It remained in the holding pattern, under control of the auto-pilot, for the next 70 minutes.
Two F-16 fighter aircraft from the Hellenic Air Force 111th Combat Wing were scrambled from Nea Anchialos Air Base to establish visual contact. They intercepted the passenger jet at 11:24 and observed that the first officer was slumped motionless at the controls and the captain's seat was empty. They also reported that oxygen masks were dangling in the passenger cabin.
At 11:49, flight attendant Andreas Prodromou entered the cockpit and sat down in the captain's seat, having remained conscious by using a portable oxygen supply. Prodromou held a UK Commercial Pilot Licence, but was not qualified to fly the Boeing 737. Crash investigators concluded that Prodromou's experience was insufficient for him to be able to gain control of the aircraft under the circumstances. Prodromou waved at the F16s very briefly, but almost as soon as he entered the cockpit, the left engine flamed out due to fuel exhaustion and the plane left the holding pattern and started to descend. Ten minutes after the loss of power from the left engine, the right engine also flamed out, and just before 12:04 the aircraft crashed into hills near Grammatiko, 40 km (25 mi; 22 nmi) from Athens, killing all 121 passengers and crew on board.