The arrests follow search warrants at four addresses in Whalley Range, Old Trafford and Bury this morning.
Two men, aged 24 and 32, were arrested on suspicion of conspiracy to supply class A and class B drugs, and possession of firearms and ammunition with intent to endanger life.They remain in custody for questioning.
Officers have seized four handguns, ammunition, cocaine and cannabis.
Superintendent Ian Crewe, of GMP’s City of Manchester division, said: “Today’s operation is part of our ongoing work to tackle the scourge of drugs and organised crime on our communities.
“Thanks to the hard work of our officers, we now have two people in custody and we have successfully removed four guns with ammunition and a large amount of drugs destined for the streets of Greater Manchester.
“Drugs blight our communities and we are committed to tackling those who supply and deal them and any associated criminality.
“We need people to take a stand against drug and gun crime, and I would urge everyone to report suspicious activity to police to help us make our streets a safer place to be.
Information can be left with police on 101 or by contacting the independent charity Crimestoppers, anonymously, on 0800 555 111.