The strikes are set to hit Frankfurt, Munich, Düsseldorf, Cologne-Bonn, Dortmund and Hanover airports as service workers' union Verdi enters a battle with the government over pay rises for the public sector.
Lufthansa's plan to cancel 895 flights - 60 percent of its usual services - will hit a total of 87,000 passengers.
In Munich 545 Lufthansa flights have been cancelled, with a further 350 cancelled at Frankfurt.
“We announced the action on Friday to take passengers into account,” Verdi boss Frank Bsirske told the Ruhr Nachrichten newspaper on Friday.
But for travellers, it's set to be a day of chaos as no long-haul flights will arrive or depart at Munich airport, with many internal and European services also cancelled.
"It's unacceptable that the effects of this strike are hitting our passengers the hardest," said Lufthansa head of human resources Bettina Volkens.
Intercontinental flights will mostly be in service at Germany's busiest airport, Frankfurt, but most internal flights and many European services are also likely to fall through.
Passengers booked on internal German flights will be able to use Deutsche Bahn trains to reach their destination or re-book their ticket at no extra cost, the airline said – even if their particular flight is not affected by the strike.
Air Berlin said that its passengers affected by the strike could re-book onto any flight on the same route between April 28th and May 4th.
The strike is set to last until 3pm on Wednesday.
Workers including mechanics, air traffic controllers, ground crew and administrators are all expected to walk off the job.
But it's the airport firefighters whose walk-out will force the flights to be cancelled at Frankfurt, Munich and Cologne-Bonn.
Without firefighters on duty, no service is possible at an airport.
“We urgently need rules for industrial disputes in air traffic,” Lufthansa's Volkens said.
The airline giant was hit by repeated strikes throughout 2015 as pilots and air crew engaged in separate battles over wages and pensions. It estimated its losses at up to €270 million for both sets of strikes – and the conflict is not yet over.