The Exiles took command just before the break when Barry Everitt set up Riki Flutey for a 40th-minute try.
They continued their domination early in the second half and led 23-8 thanks to a Philip Murphy try, converted by the impressive Everitt.
Jonny Wilkinson gave Newcastle hope with four penalties but the Exiles defence held firm for the win.
London Irish coach Brian Smith: "I'm delighted with the result, although there are still things to work on.
"Our defence was very, very good and although we struggled in the line-out early on we managed to fix it.
"We've been unlucky with some of our defeats so it was pleasing to be on the end of a narrow victory for once."
Newcastle: Burke, May, Tait, Flood, Grindal, Hoyle, J. Wilkinson, Anderson, Long, Morris, Parling, Buist, Finegan, Woods, Charvis.
Replacements: Dickson for Grindal (46), Ward for Anderson (46), Thompson for Long (58), Paoletti for Morris (65), McCarthy for Finegan (54).
Not Used: Smitson, Walder.
London Irish: Flutey, Armitage, Penney, Catt, Bishop, Everitt, Willis, Hatley, Coetzee, Rautembach, Casey, Kennedy, Roche, Danaher, Murphy.
Replacements: Strudwick for Casey (72).
Not Used: Collins, Russell, Gustard, Feaunati, Hodgson, Mordt.
Att: 10,200
Ref: Sean Davey (RFU).