Northern Ireland native McKillop retained his T37 800m title in one minute 57.19 seconds to cut 0.03 secs off his previous world record time.
Smyth equalled his world record mark of 21.05 seconds in the T13 200m final to regain his title.
Both runners will aim to make it a double success later in the week.
McKillop, a double gold medallist at last year’s London Paralympics, will be a strong favourite on Wednesday when he races in the T38 1500m final.
The 23-year-old finished more than five seconds ahead of Australia’s Brad Scott in Sunday’s 800m final.
The Irishman led the field by around 10 metres as he reached the bell in 58.01 and extended his advantage over the second lap.
McKillop’s victory meant he successfully defended the title he won two years ago in Christchurch.
“I ran 1:54 in a time trial just before I flew out here so I knew I was in good shape,” McKillop told BBC Sport.
“My aim each time I race is to cross the line first and if the time comes, that’s a bonus. I wasn’t looking for a time today, I was just going out there to win and that’s what I did.”
The fierce heat in Lyon meant McKillop had to make adjustments to his pre-race preparations
“It is definitely the hottest I have ever raced in and it is hard to run in these conditions, but it is the same for everyone,” he added.
Smyth, who missed the last championships in New Zealand in 2011, came home ahead of Namibian Nambala Johannes (21.59) and South African Jonathan Ntutu (22.09).
“I’ve taken the 200 win and hopefully I’ll be able to produce the goods again later in the week in the 100m,” said the 26-year-old Derryman.
“It’s nice to equal the world record but the main thing was to come here and win,” he added.
After Sunday’s successes, the two Northern Irishmen will have a couple of days off before aiming to complete doubles in France.
Smyth will be in action in the T13 100m heats on Wednesday morning, with the final scheduled for Thursday evening.
Once again, McKillop will not be required to run heats in the 1500m, with the T38 final scheduled for Wednesday afternoon.
McKillop set a world record when winning the 1500m in Christchurch but was not awarded a gold medal because there were only two entrants.