Among 45 people the Drug Enforcement Administration (DEA) was looking for, 12 were current or former employees of American Airlines.
A spokesman for the airline said it had a "zero-tolerance policy" for "this kind of activity".
Puerto Rico, a US territory, is a major drug shipment point in the Caribbean.
Three additional suspects were arrested in US airports, officials said.
"We have dismantled the two most significant drug operations at the airport," said Pedro Janer, acting special agent in charge of the DEA's Caribbean division.
In addition to the 12 people connected to American Airlines, warrants were issued for workers at Ground Motive Dependable, a company that provides baggage handling at the airport.
One government worker with Puerto Rico's Port Authority is also being sought.
The morning raid involved two investigations, one stretching from 1999 to 2009, and the other from 2010 to 2012.
According to the DEA, suspects in the first case would allegedly enter Luis Munoz Marin International Airport through employee entrances while carrying concealed drugs. They then passed the drugs to another person in bathrooms beyond security checkpoints.
In the second case, a group of 20 people are accused of smuggling 9,000kg (20,000lb) of cocaine by loading suitcases filled with the drug into the cargo area and ensuring their arrival at US mainland airports.
Some of the drugs belonged to Angel Ayala Vazquez, once considered Puerto Rico's top drug dealer, the DEA said.
Puerto Rico is seeking more federal funding to fight drug trafficking. US officials say more than 70% of the cocaine that arrives on the island is destined for the mainland.