In a media release today, BCCI secretary Sanjay Patel said Mohit had aggravated his bilateral shin pain.
"Mohit Sharma has aggravated his bilateral shin pain, and has therefore been ruled out of the ongoing Micromax Cup, India vs West Indies ODI series, 2014," Patel said.
"The All-India Senior Selection Committee has named Ishant Sharma as his replacement in the Indian squad," he added.
The 26-year-old Ishant last played a ODI in January this year, against New Zealand, in Hamilton. So far he has featured in 72 ODIs and has taken 102 wickets.
Mohit played in the first ODI in Kochi. West Indies won by 124 runs. Mohit went wicketless in his 9 overs, conceding 61 runs.
The second of the five matches will be played at Delhi's Feroz Shah Kotla Stadium on Saturday (October 11).