Authorities are scrambling to assess damage and respond to reports of injuries after the first, 7.5 magnitude earthquake centred near Hanmer Springs.
"On the best information we have, there have been two fatalities," Mr Key told a media conference early this morning.
Earlier, police said one person had died in Kaikoura, where a house had collapsed in the earthquake.
Police said they were also trying to get to a property at Mt Lyford, north of Christchurch, where a second person is believed to have died.
Mr Key said a Defence Force helicopter would be flying down to Kaikoura and another one would be available in Wellington.
An Urban Search and Rescue team from Christchurch was also on its way to Kaikoura by helicopter to help following this morning's quake.
Two further assessment teams had also been deployed - one to Waiau and one to Blenheim.
Two New Zealand Fire Service command units will also provide potential coordination of assessment teams as needed.
Nelson Marlborough District Health Board said five people had been admitted to Wairau Hospital by early this morning with various injuries, some described as moderate.
The first quake struck at 12.02am, at a depth of 15km.
It has been followed by a series of large earthquakes across New Zealand up to 6.2 in magnitude, which prompted tsunami alerts, causing residents of coastal areas to flee inland.
Most were in the upper South Island, in Seddon and Kaikoura, but a 4.9 magnitude earthquake hit Paraparaumu and a 4.9 hit Wellington in the early hours.
The earthquake sequence is the biggest since the 5.7 Valentine's Day earthquake, which caused cliffs in the Christchurch suburb of Sumner to fall and liquefaction in some east Christchurch areas.
Tsunami activity was detected in Kaikoura and Wellington, with initial tsunami warnings prompting sirens from Northland to Christchurch.
But the Chatham Islands and the region between Blenheim and Banks Peninsula is still prone to a marine and land threat.
Wave activity was detected in Wellington and the South Island, including a tsunami two metres or taller in Kaikoura, a wave in the north-eastern coast of the South Island, Civil Defence tweeted.
KiwiRail says all trains on the North Island Main Trunk line, south of Palmerston North, and in the South Island have been cancelled until further notice.
Ferry sailings have also been cancelled until a full assessment can be made of the terminals in Wellington and Picton.
The Kaiarahi is currently standing off Picton, and the Kaitaki and Aratere are at anchor in Wellington Harbour.
People left houses in Brighton in Christchurch, and central Wellington, and left seaside areas of Wellington including Lyall Bay for higher ground. People were evacuated from Marlborough.
The Ministry of Education advised schools and early childhood centres from North Canterbury through to Wellington would remain closed today.
It said single-story buildings required a visual check for damage, while multi-story buildings would need to be checked by an engineer.
Acting Civil Defence Minister Gerry Brownlee overnight the damage to property would become clearer at daybreak. Buildings would need to be checked to ensure they were safe.
Northern South Island
Helicopters were set to check on a train at first light this morning, which was believed to be trapped north of Kaikoura following the quakes.
Marlborough Civil Defence controller Richard McNamara said it had been difficult to assess the damage in the area overnight.
"Our helicopter will drop in and check on the driver, we've been talking to train control South Island.
"There's also a relief driver and a utility that we need to make contact with too.
"But there'll be other people on the road that will be stuck and obviously the heavy traffic between Picton [at] the interisland ferry and Christchurch will also be held up."
Mr McNamara said State Highway 1, south of Ward, was closed.
He said bridges north of Blenheim had been damaged, but there was a diversion in place.
Several people spent hours stuck on the Interislander Ferry, which was unable to dock in Picton due to a power cut.
Marlborough Civil Defence said buildings in Picton's main street were reported to be badly damaged, and the earthquake had caused liquefaction on the Picton foreshore.
There was a diversion in place on SH1 between Picton and Blenheim, which was open for some vehicles but heavier vehicles cannot get through and were reported to be banked up for several kilometres along the highway.
Ferry movements have been suspended for the day.
Picton residents have been asked to conserve water as one of the town's reservoirs was leaking.
An evacuation centre is being opened at the Waikawa Marae .
The Nelson Marlborough District Health Board said by early this morning five people had been admitted to Wairau Hospital with various injuries, some described as moderate.
Spark said its phone networks in Clarence, Kaikoura, Weld Cone, Waiau and Eltham in the South Island have been affected. People should text rather than call if possible, it said.
Houses were reported to be damaged in Kaikoura and chimneys down in Culverden.
Power went out in many areas including Picton, Blenheim and Havelock.
Police said they were trying to get access to the Mt Lyford property where one person was thought to have died.
"A further casualty has been reported, which is believed to be a fatality," police said.
Three evacuation centres were open in Christchurch. At 5am there were 230 people at Linwood College, 50 at Mairehau School and 25 at Akaroa School Hall.
Hotel guests in central Christchurch were evacuated. More than 100 people stood on the footpath opposite the Christchurch Casino, while at least 100 hotel guests are outside the Novotel, opposite the Christ Church Cathedral.
Alan Vincent was on the water near Lyttelton near Christchurch when the quake struck. He said it felt like "giants shaking the living daylights out of the boat".
Cheviot firefighter Chris Hill said the roads were "a bit cut up".
A temporary boil water notice has been issued in Hurunui. A welfare centre was set up at the Amberley Pavilion.
Christchurch police have set up roadblocks to stop people going to coastal areas while a tsunami warning was in place.
Robin, from Christchurch, said the earthquake was a "wake up call".
New Brighton resident Dean Kozanic evacuated his home as a precaution because of the tsunami warning. He said many residents in the suburb had been doing the same.
Power was cut in North Canterbury, from Kaikoura to Cheviot. The Hurunui District Council said Rotherham and Waiau were isolated by slips and damage to the bridge.
Wellington Civil Defence has advised people not to go to work in the central city and Lower Hutt this morning.
Several multi-story buildings received damage - both internally and structurally - and glass fell into streets.
Controller Bruce Pepperell said early indications were that a number of major buildings showed signs of structural stress and the strong quake would likely have caused a mess inside.
Power was out in some areas, and Mr Pepperell said widespread liquefaction has been reported on reclaimed land around the city's waterfront.
Mr Pepperell said the capital's suburban rail network would not be operating until further notice, while rail tracks, bridges and tunnels are checked, and buses are unlikely to replace the trains.
RNZ presenter Simon Morton, who lives on the south coast in Wellington, evacuated from his house after noticing the tide dropping away. Other people had joined him in going to higher ground.
Victoria and Massey university campuses in the capital would be closed until midday, with Massey saying exams would be postponed until further notice.
People who evacuated in the Wellington city centre could find temporary refuge at the BizDojo Centre on 115 Tory Street, or Houghton Valley School further out of the city.
Residents in coastal areas were urged to stay inland or on high ground. Affected spots include seaside areas of Wellington's south coast, Seatoun and Eastbourne.
The state of emergency in Dunedin has been lifted after civil defence evacuated about 50 households in seaside communities.
The controller for Clutha district, Charles Hakkaart, said the main evacuations were in low-lying houses in Pounawea, Taieri Mouth and Toko Mouth.
Civil Defence in Otago says the land-based threat to the eastern coasts had passed and people were being allowed to go home.