He said he drove the car in one direction to test it, but then asked Thurman to drive it the other way.
He said he didn't realise there was a twist in the road coming back. Thurman posted footage of her crash on Monday.
The director said failing to test the route one more time was "one of my most horrendous mistakes".
Thurman suffered neck and knee injuries in the accident.
In a New York Times interview published over the weekend, Thurman said she had worries about the state of the car, but that Tarantino had persuaded her to go ahead with the scene.
In an interview with Deadline Hollywood, the director said he heard "Uma was trepidatious about doing the driving shot" but added: "None of us ever considered it a stunt. It was just driving. Maybe we should have but we didn't."
He said he drove down the road to check it was OK and thought, "this is going to be okay. This is a straight shot... no hidden S-curves".
He added: "I was very happy, thinking, she can totally do this, it won't be a problem.
"I came in there all happy telling her she could totally do it, it was a straight line, you will have no problem. Uma's response was 'OK'. Because she believed me. Because she trusted me... I told her it would be safe. And it wasn't. I was wrong.
"I didn't force her into the car. She got into the car because she trusted me. And she believed me."
He said they decided Thurman should drive the car down the same road in the opposite direction because the light would be better as it was getting towards the end of the day.
"I thought, a straight road is a straight road and I didn't think I needed to run the road again to make sure there wasn't any difference, going in the opposite direction.
"Again, that is one of the biggest regrets of my life. As a director, you learn things and sometimes you learn them through horrendous mistakes. That was one of my most horrendous mistakes, that I didn't take the time to run the road, one more time, just to see what I would see."
He said it was "just horrible" when he saw her crash.
"It was heartbreaking. Beyond one of the biggest regrets of my career, it was one of the biggest regrets of my life.
"It affected me and Uma for the next two or three years. It wasn't like we didn't talk. But a trust was broken."