The undefeated Manchester fighter, 26, was awarded a 117-110, 115-112, 117-110 verdict over his Liverpool opponent.
Flanagan was docked a point in the eighth round by referee Phil Edwards for using his forearm, after receiving repeated warnings for pushing.
But it made no difference at the Liverpool Echo Arena as 32-year-old Mathews slipped to a 10th defeat.
Flanagan has now won all 30 of his professional fights.
His promoter, Frank Warren, says "the obvious next fight" for him is against fellow Mancunian and holder of the WBA lightweight world title Anthony Crolla.
"We've made him a big offer," said Warren on Box Nation. "Let the two of them fight. There's no problem from our end. It's a fight that could be made.
"Other than that I like the Linares fight," he added, referring to Venezuelan three-weight champion Jorge Linares, who currently holds the WBC version of the world lightweight title.
Crolla is scheduled to defend his WBA lightweight title against Ismael Barroso at the Manchester Arena on 7 May.

Between the first quarter of 2016 and the same period this year, the amount of goods sold in Scotland rose by 0.2%, compared with British growth of 2.1%.
Meanwhile, the value of shop sales north of the border grew by 1.8%, while Britain saw a rise of 4.8%.
The figures were included in the latest Retail Sales Index for Scotland.
Scotland outperformed Britain in the first three months of this year, however, in both value and volume terms.
The first quarter saw the volume of sales in Scotland fall by 0.4%, while the figure for Britain showed a drop of 1.4%.
And while the value of sales across Britain flat-lined, Scotland saw growth of 0.5% between January and March.
Commenting on the figures, Scottish Retail Consortium director David Lonsdale said: "The improvement in the headline figure for the total value of retail sales in the first quarter of this year is encouraging at first glance, but it looks less rosy once falling shop prices are taken into account.
"Indeed, shop prices have fallen each month for the past four years which demonstrates that retailers are having to work ever harder to maintain let alone grow sales values."
Euan Murray, from Barclays Corporate Banking, said: "Increased supply chain costs and issues could go some way to explaining the falling figures in this quarter - from the bad weather in Spain affecting food imports to the weak value of sterling, you don't have to look far for a reason.
"The sector has also had the added pressure of a later Easter, which could have resulted in less consumer spend in quarter one."
He added: "With 36% of UK e-retail sales via mobile, retailers must invest in their online and mobile shopping platforms to improve the user experience and drive growth.
"However, with inflation in the UK set to accelerate faster than earnings growth for the first time since 2014 and consumers planning to spend less on every category with the exception of grocery, it is looking like it's going to be an uphill battle for the high street."
Terry Flanagan retained his WBO world lightweight title with a unanimous points decision over Derry Mathews.
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Retail sales in Scotland have grown much more slowly over the past year than in Great Britain as a whole, according to new figures.