The Lightning won their sixth match in succession and their 10th of out of 14 in all as they completed their group campaign in comprehensive fashion thanks mainly to impressive performances from Usman Khawaja and Kyle Jarvis, both playing for the first time in Twenty20 this season.
Australian overseas batsman Khawaja, playing in place of the rested Tom Smith, top scored with 44 off 25 balls in a competitive 164 for eight, although the hosts should have posted more on a typically abrasive Old Trafford surface.
Durham’s reply never got going as they reached 137 for seven thanks mostly to Phil Mustard’s 49 at the top of the order.
Khawaja and Ashwell Prince had got Lancashire off to a flyer with an opening stand of 84 in 7.1 overs, their best of the season.
Jarvis led a much-changed Lightning bowling attack, minus Junaid Khan and Andrew Flintoff, with 2-25 from four overs.
Khawaja and Prince took advantage of some poor leg-side bowling before Durham, led by their experienced West Indian off-spinner Gareth Breese, improved with some effect to restrict Lancashire to a total within reach.
The wicket of Prince, bowled by Breese with the first ball of the eighth over, was the first of five to fall for 23 runs in 32 balls as the Lightning slipped to 107 for five in the 13th.
Breese struck three times for 19 in four overs while his partner in crime Paul Collingwood finished with 2-21.
Khawaja was strong playing to leg before he holed out to deep mid-wicket off Breese in the 10th over, having hit seven boundaries.
Steven Croft’s 31 off 28 balls, including the only six of the innings, helped to get Lancashire moving again but three late wickets, including two for the medium pace of Keaton Jennings, ensured there was not too much damage done.
Durham’s reply got off to a slow start at 11 without loss after three overs as Croft, Kabir Ali and Jarvis all bowled tight overs.
That pressure paid off in the fourth over when Scott Borthwick chipped Wayne White to mid-off with the score on 12.
Jarvis struck in the next when Calum MacLeod found mid-on as Durham fell to 25 for two on their way to a powerplay score of 27 for two, a score in stark contrast to Lancashire at the same stage.
Michael Richardson was caught behind off Croft in the eighth over before Durham reached halfway at 49 for three with another 116 still needed.
Collingwood miscued and skied Jarvis to point as Durham fell to 66 for four in the 13th before Mustard holed out to deep backward square-leg against Ali with the last ball of the 17th.
Durham, at 108 for five, needed 57 off the last three and Ali struck twice in the last as he comfortably defended 35 and finished with 3-19 himself.
Khawaja said: "It was my first T20 and it was a lot of fun.
"It was a bit touch-and-go there after we batted but the boys bowled really well.
"I've watched every single game here and we haven't looked like losing. Some of the games we've been getting 200 easily and that's why I was a bit surprised we only got 160. It was a bit odd.
"There's a really good vibe in the changing room, especially when the T20s come around. We've finished first in the table, we've beaten the best sides and we're very confident."