Sehwag scored 309 and Tendulkar was unbeaten on 165 as India, resuming at the lunch score of 467 for two, moved to 588 for four by tea on the second day at the Multan stadium on Monday.
It is already India's highest total against Pakistan, surpassing the 539 for nine declared at Chennai in 1961, and sets the stage for an Indian domination of the rest of the match.
Sehwag, who batted for nine hours and hit 39 boundaries and six sixes, was finally dismissed in the post-lunch session when a tired edge off Mohammad Sami was caught in the slips.
The 25-year-old, playing his 21st Test, joined a select band of 17 batsmen to score triple centuries in Test cricket. Australia's Don Bradman in the only one to have done it twice.
The swashbuckling opener reached the landmark by lofting Saqlain Mushtaq over the long-on ropes for his sixth six, but fell soon after.
Venkatsai Laxman, whose Indian record of 281 against Australia at Calcutta in 2001 was overtaken by Sehwag, managed only 29 when he was run out by a superb throw from the fence by Yousuf Youhana.
Left-handed Yuvraj Singh, replacing the injured captain Sourav Ganguly for the match, gave Tendualkar company at tea on 11.
Sehwag and Tendulkar, who came together before tea on the first day, put on 336 for the third wicket to compile India's best partnership against Pakistan.
The stand bettered the previous record of 200 achieved by two pairs against Pakistan: Gavaskar and Kris Srikkanth at Chennai in 1987 and Ravi Shastri and Sandeep Patil in Faisalabad in 1984.
Tendulkar's 33rd century surpassed retired Australian captain Steve Waugh's tally of 32 and left the Indian champion just one short of country-mate Sunil Gavaskar's world record of 34.
He has so far hit 19 boundaries.
Pakistan's bowlers, who struggled for the second successive day on the lifeless track, were let down further by poor catching close to the wicket.
Sehwag, who was missed twice on the first day, escaped twice in one Shabbir Ahmed over on the second morning when Taufiq Umer at slip and wicketkeeper Moin Khan failed to take sharp chances.
Express paceman Shoaib Akhtar went for 0-102, Shabbir conceded 0-122, Sami had 2-92 and Saqlain Mushtaq returned with 1-173 against his name.
India, on their first full tour of Pakistan since 1989, won the preceding One-day series 3-2.