The two, who were both in their 40s, were discovered on Friday at a home in Standoff on the Blood reserve.
Two others were taken to hospital after taking what's believed to have been a potent batch of fentanyl.
The illegal drug is sometimes sold to unsuspecting buyers as OxyContin or heroin and has been linked to more than 100 deaths in Alberta last year.
Charles Shouting, who is 34, Jessica Good Rider, who is 26, and 41-year-old Bobby Weasel Head are charged with drug trafficking and criminal negligence causing death.
Blood Tribe police Chief Lee Boyd says enough is enough.
"If you are selling drugs in this community, we are going to come after you," he said Monday. "If someone dies from the drugs you have sold them, we will do everything in our power to hold you legally responsible for your actions."
Fentanyl can be many times more powerful and toxic than morphine and can be mixed into other street drugs.
Police say they have been seizing record amounts of fentanyl in communities around Alberta, including more than 88,000 tablets since last April.
Fentanyl made by pharmaceutical companies is used to treat severe pain or to manage pain after surgery. Illegally made fentanyl is made in clandestine drug labs and sold in pills or powder.
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