Sister Serena Williams, fresh from her Olympic gold medal success in London, ground out a 6-3 6-4 win over determined Greek Eleni Daniilidou.
Venus served for the match twice in the second set, when up 5-4 and 6-5, but Kirilenko, the 12th seed, fought well to push the first-round contest into a third set.
The American was on top throughout the decider, though, showing no signs of the physical ailments which cut short her campaign in the US Open last year.
The seven-times Grand Slam singles champion pulled out of last year's US Open citing an auto-immune disease, Sjogren's Syndrome, which causes fatigue and joint pain.
"I'm doing a lot better than this time last year," Williams said. "So much better. So much better than a couple months of ago as well. I also am learning to deal with everything a lot better.
"If I wake up and I don't feel great, then I would panic and lose my match 2-1. I had a few 2-1's this year, too, but I had to take those losses in order learn and get better.
"Now I realise that I just kind of hang in there if I'm not having the best day and still try to get the win."
Williams had to skip the Australian Open in January and her comeback did not begin in earnest until she reached the quarter-finals at Miami in March.
Not that Williams is out of the woods yet. She continues to work with her medical team to reduce the impact of the disease.
"I'm trying different things all the time," she said.
"Nothing can prevent bad days, but the bad days aren't as bad as they used to be.
"It's a work in progress. My main goal is to be 100 per cent, but it's not like it goes away. It's still in my body trying to fight against me, but I'm fighting it as well."
Slovakia's Daniela Hantuchova fought back in the second set, surviving match point, to beat China's Zheng Jie 2-6 7-6 6-3 and will next face Italian Sara Errani.
Australian world number six Samantha Stosur survived a scare against Spain's Anabel Medina Garrigues before winning 6-3 6-7 6-4.
Stosur had to come back from 0-4 down in the third and did so by winning six straight games.
"I kind of let myself down with some hitting errors too early and got in that big hole," she said. "I thought, I can still regroup and close that gap just a little bit. If you can do that, then you never know what can happen. I got on a roll and managed to squeeze it out."
The 15th seed Nadia Petrova also went out. She retired injured while behind 7-6 (8) 3-1 to fellow Russian Ekaterina Makarova.
In the tournament's first second-round match, fifth-seeded Angelique Kerber of Germany needed three sets to eliminate Timea Babos of Hungary 3-6 6-1 6-2.