The so-called narco-sub was reportedly en route to the Iberian Peninsula when it was seized in recent days.
Footage released by authorities shows police and navy personnel surrounding the vessel before boarding it, confiscating the Class A drug, and arresting the crew.
The four suspects — identified as two Ecuadorians, a Venezuelan, and a Colombian — appeared in court in the Azores on Tuesday and were remanded in pre-trial custody, police confirmed.
Vítor Ananias, head of Portugal's police unit to combat drug trafficking, told a press conference that their different nationalities showed the organisation behind them was not just based in one country.
The Lisbon-based Maritime Analysis and Operations Centre (MAOC) said it had received information in recent days indicating that a criminal organisation was in the process of dispatching a submersible loaded with cocaine destined for Europe.
A few days later, a Portuguese ship successfully located the submersible approximately 1,000 nautical miles (1,852km) off the coast of Lisbon, in an operation backed by the UK's National Crime Agency and the US Drug Enforcement Administration.
Having seized the vessel, the navy said it could not be towed back to shore due to poor weather and its fragile construction, and it later sank in the open sea.
