Kastor dominated the race as she shattered the American record of 2hrs 21mins 16 secs she set three years ago in London when she finished third behind Paula Radcliffe.
The world record-holder did not defend her title because of a foot injury.
Britain's Mara Yamauchi ran a personal best to come home sixth in 2:25:13 - a time which puts her second behind Radcliffe on the British all-time list.
She said: "I was struggling at 17 miles because I was out on my own. I had to keep it together till the end.
"The crowd support was good despite the weather and the conditions were perfect for a fast time. I'm pleased that I ran a personal best."
Kastor's confident front-running display saw her shake off Chepkemei before the 17-mile mark.
The Olympic bronze medallist, paced to 23 miles by male training partner Mike McKeeman and then Kenyan Henry Tarus, never looked back after the decisive break.
Her only other marathon victory was in Chicago last year and she becomes the first American to win the London race.
Women's London Marathon:
1. Deena Kastor (United States) 2 hours 19 minutes 36 seconds
2. Lyudmila Petrova (Russia) 2:21:29
3. Susan Chepkemei (Kenya) 2:21:46
4. Berhane Adere (Ethiopia) 2:21:52
5. Galina Bogomolova (Russia) 2:21:58
6. Mara Yamauchi (Britain) 2:25:13
7. Constantina Dita (Romania) 2:27:51
8. Salina Kosgei (Kenya) 2:28:40
9. Margaret Okayo (Kenya) 2:29:16
10. Eri Hayakawa (Japan) 2:31:41
