The nature reserve will be the largest of its kind in the county and will also be the ninth largest in England.
The 'Wild Ennerdale National Nature Reserve' will cover 3000 hectares of landscape including water, forests, and mountains.
The Wild Ennderdale partnership has brought together Forestry England, National Trust, United Utilities and Natural England to allow natural processes to shape the ecology and landscapes within the valley.
Tony Juniper, chair of Natural England said: "Wild Ennerdale is a diverse and varied landscape which supports some of our most unique and precious wildlife, including red squirrels, the freshwater pearl mussels that dwell in the river there and which can live for 100 years.
"And the Arctic charr – a fish that has hung on in the valley since the last Ice Age.
"We have been working with partners for some years to improve this already amazing place and its declaration as a national nature reserve will enhance the spectacular landscape, wildlife and habitats, safeguarding them for the future while providing space for people to get close to wild nature."
Ennerdale is the 221st site to be confirmed to be formally recognised as a nature reserve with the first in England created in 1952.
The UK government currently have a legally binding target to halt the decline of wildlife population through a target for species abundance by 2030.
Natural nature reserves (NNR's) were created to protect some of England's most important habitats, species and geology, provide research opportunities, along with learning about nature conservation benefits for society.
Rachel Oakley, of the wild Ennerdale partnership, she said: "We are constantly reminded of the nature and climate crisis we face now and for the future and this announcement shows how working together and prioritising nature can reap rewards for us all.
"These landscapes are constantly evolving and need to be ‘fit for purpose’ to adapt and respond to the many challenges we face.
"Nature can thrive if given space and a helping hand and we are seeing tangible results of that in Ennerdale."
Want a quick and expert briefing on the biggest news stories? Listen to our latest podcasts to find out What You Need To Know...