At least one person died every day in 2017 due to a drug overdose, according to the latest figures from the Health Research Board.
The HRB says that cocktails of drugs are of particular concern as it can lead to complications and increase the risk of fatal overdose.
A cocktail of drugs contributed to three-in-five of the 376 deaths.
Many of those who died in 2017 were men, typically in their 30s or 40s.
Alcohol contributed to roughly one third of all overdose deaths in 2017, while 61 people died from alcohol poisoning alone.
Prescribable drugs were used in two-thirds of overdose deaths.
The data also shows that cocaine-related poisoning continues to rise, from 42 deaths in 2016 to 53 in 2017.
The figures also show that 196 people took their own lives in 2017.
Research Officer at the HRB, Ena Lynn, said there is no county in Ireland that has not been affected by drug deaths.
Speaking to RTÉ's Morning Ireland, Ms Lynn said the majority of drug-related deaths are caused by people taking a cocktail of drugs, including alcohol.
"The most common drugs are what we call prescribable drugs. These drugs which are mainly methadone, valium, zanax. When they are misused or taken as part of a cocktail, outside medical supervision, they can be fatal.
"Alcohol has contributed to one in three poison deaths in Ireland in 2017. It still remains the main single drug implicated in poison deaths in Ireland, either on its own or as part of a cocktail of drugs."
Ms Lynn said there was been an increase in cocaine and ecstasy deaths in 2017.
She said that cocaine "mirrors our economy in Ireland", pointing out that the peak in cocaine poisoning deaths was in 2007 at the height of the Celtic Tiger.
She added that there is an increased supply of illicit drugs on the market and they are stronger.
"Since 2010 we have seen a steady increase in poison deaths involving cocaine, corresponding to our increase in our economy," she said.