“It wasn’t an easy match tonight,” said the 37-year-old, seeded just 16.
“So I knew ‘Serena, you’ve got to come out hot, you’ve got to come out firing, she’s a really good player and I haven’t had many matches since last year’.”
Williams is bidding to match Margaret Court’s record of 24 Grand Slam crowns, and win an eighth in Australia, on her first return to Melbourne Park since lifting the trophy in 2017 while pregnant.
Serbian top seed Djokovic is also looking to make history by winning a seventh title.
He was too good again for France’s Tsonga, who he beat in 2008 final, rolling through 6-3, 7-5, 6-4.
“You could feel the tension on court at the beginning. We felt a lot of emotion and tried to play a great game,” said Djokovic as the memories of that tense final came flooding back.
In contrast, world number one Simona Halep staggered through against American Sofia Kenin 6-3, 6-7 (5/7), 6-4 – her second three-set test in a row.
“I have no idea how I won this, it’s so tough to explain what happened on court,” said the French Open champion, who now meets Venus Williams after the 38-year-old rolled back the years to beat France’s, Alize Cornet.
In another titanic battle, Canadian Milos Raonic ousted 2014 champion Stan Wawrinka in four tightly-contested sets that all went to tie-breaks, while eighth seed Kei Nishikori was stretched to a draining five sets against Ivo Karlovic.
Seventh seed Dominic Thiem limped out when he retired while losing 7-5, 6-4, 2-0 to young Australian wildcard Alexei Popyrin.
Zverev hailed as a flag-bearer for the next generation, also struggled against veteran world number 36 Jeremy Chardy, before putting him away 7-6 (7/5), 6-4, 5-7, 6-7 (6/8), 6-1.
Amid rain delays and drawn-out matches, Spain’s Garbine Muguruza and Britain’s Johanna Konta didn’t get on court until half-past midnight – the latest start to a match in the event’s history.
US Open champion and fourth seed Naomi Osaka had it relatively easy, sweeping past Slovenia’s Tamara Zidansek 6-2, 6-4 with the roof closed on Margaret Court Arena due to the rain.
The 21-year-old’s breakthrough at Flushing Meadow over Serena Williams last year made her a new standard bearer for tennis in her Japanese homeland and Asia, and she is working hard on living up to the hype.
“I thought I served alright, this was my first time playing her and I’m just happy to win, to be honest,” Osaka said after setting up a clash with Taiwan’s Hsieh Su-wei.
In contrast, Asia’s top-ranked men’s player Nishikori needed an energy-sapping 3hr 48min to get past big-serving Croat Karlovic 6-3, 7-6 (8/6), 5-7, 5-7, 7-6 (10/7) in humid conditions.
Sixteenth seed Raonic emerged the victor against Wawrinka, a three-time Grand Slam champion who is on the comeback trail from injury.
The Swiss, unseeded for the first time since his debut in 2006, fell 6-7 (4/7), 7-6 (8/6), 7-6 (13/11), 7-6 (7/5).
Despite being seeded six and seven respectively, neither Elina Svitolina or Karolina Pliskova has progressed further than the last eight at the Australian Open.
But self-assured Svitolina is bubbling with confidence after dismantling Viktoria Kuzmova 6-4, 6-1, while Pliskova woke up after losing the first set to race past Madison Brengle 4-6, 6-1, 6-0.
Other women through included Italy’s Camila Giorgi and China’s impressive Wang Qiang. Men still in the hunt included Croat Borna Coric and Spain’s Pablo Carreno-Busta.