The pair join Landon Donovan and Brek Shea, who were sent home from the team's training camp on Tuesday by coach Juergen Klinsmann after reporting with injuries, as absentees for the clash in St. John's.
Castillo has returned to his club with a foot injury but Johnson, who has flu, could be fit for Tuesday's game against Guatemala in Kansas City, their final match in the third round of CONCACAF qualifying for the 2014 finals in Brazil.
"Obviously it's a difficult situation losing Fabian for the Antigua game and Edgar being unavailable for both," said Klinsmann. "We were in a similar situation for the first match against Antigua & Barbuda in June, and we will be prepared."
The U.S., Jamaica and Guatemala are all on seven points in Group A, with the top two going through to the final qualifying round of six teams next year.
The top three nations in that round automatically qualify for the 2014 World Cup finals. The fourth placed side will meet the Oceania champions in a playoff.