Officers became suspicious and began making enquiries last summer after large parcels of MDMA destined for Europe, Asia and the US were intercepted.
In all, the NCA said 90kg of MDMA, 134kg of amphetamine and more than 6,000 Diazepam/alprazolam tablets, with a combined street value of £4.3m, were recovered during its investigation.
Analysis of encrypted messages led police to identify suspects it believed were involved in selling the drugs and laundering the money earned through black market trading using cryptocurrency.
Two men, aged 24 and 31, were arrested on Thursday in South Shields and Hebburn, South Tyneside, on suspicion of importing and supplying class A, B and C drugs.
An address in Epsom, Surrey, was also searched, as were several other addresses in South Shields.
Officers also seized mobile phones, computers and drug-packaging paraphernalia in an operation that had the support of US law enforcement.
Investigators discovered the drugs were being imported from the Netherlands and sold on using the dark web under four handles: HundredsUK, Hundredsandthousands, Sundaefundae and 100and1000s.
Packages containing MDMA, which were intercepted by NCA and Border Force officers in June and July last year, were destined for addresses in the UK, US, Israel, Norway, Thailand, Hong Kong and Malaysia.
“This action against an organised crime group supplying drugs via the dark web has dismantled a well-established operation,” NCA operations manager Martin Clarke said.
“We have worked closely with partners in the US to target the individuals involved, who are ultimately preying on the vulnerable and destroying communities.
“This investigation shows that those who try to use the dark web and encrypted communication devices to anonymously commit crimes can be identified.
“There are two people from South Shields we are still seeking, who we believe are overseas.
“They know they are wanted and I would encourage them to hand themselves in.”