The 30-year-old from County Londonderry moved clear at the bend and won comfortably in 21.41 seconds.
Johannes Nambala of Namibia was second in 21.81 with Poland's Mateusz Michalski clocking 21.86 in third.
Smyth, who won the T13 100m final at London Stadium on Sunday, has now secured five world titles.
"I first came on the scene in 2005 and won golds all the way - I really would love to continue that," said a delighted Smyth
"I just want to be the best I can be and that's what drives me."
The visually-impaired athlete was a double Paralympic gold medallist at the same stadium in 2012.
Smyth is unbeaten at Paralympic level since beginning his international career at the 2005 European Championships.
Ireland's Jason Smyth completed a sprint double at the World Para-athletics Championships with victory in the T13 200m final at London Stadium.