The British number one has made a habit of being sucked into long matches in 2022 and she was unable to find a way through against the world number 53, going down 3-6 6-4 7-5.
Raducanu made another fast start and Siniakova seemed to be struggling with the heat and humidity, calling the trainer after only five games.
But the Czech rallied from 1-3 down to take the second set. Raducanu looked to have turned the tide back in her favour when she moved 5-3 ahead in the decider, but she ran out of steam at the end.
Raducanu said: “It was a long match. Very long rallies. I thought that she played really good. There was some good tennis on both sides, to be honest, but obviously it sucks to lose that one.”
It was another demonstration that the US Open champion has a lot of physical work ahead as she adapts to life on the WTA Tour.
She said of her struggles: “It’s a challenge, for sure. It takes a lot out of you to just keep bouncing back from it.”
While there was dejection for Raducanu, Heather Watson claimed her best victory by ranking for more than two years with a 4-6 6-3 7-6 (4) success against 20th-ranked Elina Svitolina.
It is a timely good run for Watson, who recently dropped out of the top 100, and sees her follow in the footsteps of her compatriot Harriet Dart after she also beat Svitolina in Indian Wells last week.
Watson told Amazon Prime Video: “I love this tournament. I’ve been coming here for so long. I just love it here, I feel like it’s home.
“I’m really happy that I’m coming back into form this year. I was just thinking at the end that my fitness got me through that match. I’m really glad I held my nerve and was able to get over the line.”
Elsewhere, Naomi Osaka claimed her first victory over a top-20 player for a year, easily dispatching three-time grand slam champion Angelique Kerber 6-2 6-3.
The former world number one has dropped to 77 in the rankings but played a strong match to set up a third-round clash with Karolina Muchova, who is returning from an injury-enforced break and upset Leylah Fernandez.
Osaka said: “I’m definitely really happy with how this match went. I think she’s beaten me the last three times we’ve played, so to turn that around and be able to do that in two sets is really nice.”
Danielle Collins played her first completed match since reaching the Australian Open final, beating Anna Bondar of Hungary 6-3 3-6 6-4, while eighth seed Ons Jabeur saw off Magda Linette 7-6 (1) 6-2.
Simona Halep and Garbine Muguruza pulled out of the tournament on Thursday with thigh and shoulder problems, respectively.
Meanwhile, former US Open champion Dominic Thiem has announced he will return to action at next week’s Challenger tournament in Marbella after nine months out with a wrist injury.