The tourists, who selected debutant Samit Patel at the expense of Ravi Bopara, took three quick wickets at the start of the day, but Jayawardene's stunning century hauled his side back into the contest.
Sri Lanka ended the day strongly with England left frustrated after a highly successfully but exhausting day saw Monty Panesar drop two catches off Jayawardene in the blistering heat at the scenic Galle International Stadium.
England new ball bowlers James Anderson – who became the sixth man to take 250 Test wickets for England – and Stuart Broad rocked Sri Lanka in their opening spells, claiming three quick wickets before the hosts staged a recovery.
On a dry batting track, Sri Lanka's delight at winning the toss and taking first lease of the wicket was short-lived as they slumped to 15 for three within the first 24 minutes of play.
Anderson struck first, forcing Lahiru Thirimanne to edge a catch to Graeme Swann at third slip for three, when the batsman poked at a delivery without moving his feet.
The Lancashire paceman struck again with his next delivery, sending back Kumar Sangakkara – the number one-ranked Test batsman – for a first-ball duck when he pushed at a full-length delivery for an edge to wicket-keeper Matt Prior.
Jayawardene survived Anderson's hat-trick delivery but Broad struck in the following over when he had Tillakaratne Dilshan (11) edging a catch to Andrew Strauss at first slip.
England used both their reviews inside the first 23 overs, but both were unsuccessful.
Things could have been even worse for Sri Lanka but Jayawardene got a reprieve when batting on 64. A Swann delivery jumped off a good length, surprising the batsman and Anderson at slip failed to hold on to the edge as the ball sailed over his head.
Sri Lanka lost Thilan Samaraweera (20) immediately after lunch when he was run out in the third over of the afternoon, and he was unfortunate to depart when a straight drive by Jayawardene off Anderson brushed the bowler's right hand and hit the stumps with the batsman out of his crease.
England picked up a bonus wicket when Dinesh Chandimal played an awful stroke across the line and top-edged a catch to Ian Bell at cover for 27 to give debutant Samit Patel his first Test wicket.
Prasanna Jayawardene shared a 42-run partnership with his skipper, before he was trapped lbw to Anderson – who picked up his third wicket and drew level on strikes with the great Brian Statham – for a hard-fought 23.
Suraj Randiv could only muster 12 runs before he was clinically run-out by Strauss, who found an inspired direct hit to leave the batsman well short of his ground.
Rangana Herath became the eighth wicket to fall as he was trapped lbw by Patel – who claimed his second wicket with another fleeting spell on a memorable day for the portly Nottinghamshire all-rounder.
It was then left to Chanaka Welegedara (10) to become Mahela Jayawardene's accomplice as their partnership was left unscathed at stumps.
The Sri Lanka skipper ended the day on 168, but should have been caught twice in successive overs as the hapless Panesar grounded regulation chances to snaffle the dangerman.
England's bowlers have further work to complete on day two, while Strauss was left to reflect on a day in which – but for one sublime innings from a prolific and inspired batsman – his side had the better of their hosts.