Emergency services took three hours to extinguish the fire at the Chempark site, home to chemicals companies Bayer and Lanxess, that flared up after the blast at 9:40am, park operator Currenta said.
"We are deeply shaken by the tragic death of one colleague," said Chempark chief Lars Friedrich, adding that the search was going on for four others who were still missing.
He said 16 people had been injured, with one facing possible life-threatening injuries.
"This is a tragic moment for the city of Leverkusen," said Uwe Richrath, mayor of the city, which lies north of Cologne.
The area was sealed off and surrounded by emergency vehicles. Nearby roads, including motorways, were closed.
Police told residents living nearby to stay indoors and shut doors and windows in case there were toxic fumes. Currenta said locals should also turn off air conditioning systems while it measured the air around the site for possible toxic gases.
Chempark's Friedrich said it was not clear what had caused the explosion the led to the fire that began in a tank containing solvents.
"A precise analysis is not yet available so we have not withdrawn the warning," said Friedrich.
Sirens and emergency alerts on the German civil protection agency's mobile phone app warned citizens of "extreme danger".
Leverkusen is less than 50 kilometres from a region hit last week by catastrophic floods that killed at least 180 people.
More than 30 companies operate at the Chempark site in Leverkusen, including Covestro, Bayer, Lanxess and Arlanxeo, according to its website.
Bayer and Lanxess in 2019 sold Chempark operator Currenta to Macquarie Infrastructure and Real Assets for an enterprise value of 3.5 billion euros. (Reuters)