The Indians, playing their first Test on Pakistan soil since 1989, plundered 356 for two by stumps on the opening day of the Multan Test after stand-in captain Rahul Dravid elected to take first strike.
Sehwag batted as if trying to make up for lost time, striking 30 boundaries and five sixes in his sixth three-figure knock from 21 matches.
He surpassed his previous best of 195 against Australia at Melbourne last year, and also beat Sanjay Manjrekar's 218 at Lahore in 1989 as the highest score by an Indian batsman against Pakistan.
The 25-year-old put on 160 for the first wicket with Delhi teammate Aakash Chopra and 183 for the unbroken third with Sachin Tendulkar, who returned unbeaten on 60.
Sehwag was stranded on 199 for nine deliveries, before flicking the 10th off Abdul Razzaq for two runs amidst loud applause from some 5,000 spectators at the Multan stadium.
The tourists put on 104-0 by lunch and moved to 228 for two by tea as the Pakistani bowling wilted under the hot sun on the unresponsive wicket.
Fiery fast bowler Shoaib Akhtar went wicketless for 60 runs, Mohammad Sami conceded 1-54 and veteran off-spinner Saqlain Mushtaq was thrashed for 1-123 from 23 overs.
Pakistan were left to rue two missed chances off Sehwag's rampaging blade on either side of lunch.
Sami put down a skier at mid-wicket off Saqlain just before the break and then Saqlain himself failed to latch on to a low catch at mid-on off Akhtar soon after resumption.
Chopra, content on playing second fiddle to Sehwag, made 42 when he was caught in the leg-trap off Saqlain.
Dravid top-edged a hook off Sami to square-leg, finally giving Pakistan captain Inzamam-ul Haq something to smile about on his home ground.
But Tendulkar stepped in to continue Pakistan's frustration with his 38th half-century from 112 matches.
Sehwag, 76 at lunch, reached the coveted three-figure mark in fitting style, guiding the express pace of Akhtar over third man for his fourth six.
He had earlier launched the historic Test series by flicking his second delivery from Sami to the square-leg boundary.
The swashbuckling opener smashed Shabbir Ahmed over third man for six and brought up his half-century by hitting Akhtar for his ninth boundary.
Chopra, who was on nine when Sehwag reached 50, finally made an impact when he flicked Akhtar for his first four.
The run feast continued for the rest of the day as Sehwag, and later Tendulkar, smashed the tired bowling to all parts of the field.
Both teams went in with three seamers and one spinner on a grassless wicket that promises to throw up a lot of runs.
The Indians, without injured skipper Sourav Ganguly, left out Murali Kartik and Ajit Agarkar from the 13 named on Saturday. Leg-spinner Anil Kumble joined the attack with seamers Zaheer Khan, Irfan Pathan and Laxmipathy Balaji.
Pakistan preferred Saqlain to leg-spinner Danish Kaneria.