After two holes, Casey had the lead to himself at Muirfield Village in Dublin, Ohio. He went on to another six-under-par 66 to build a three-shot lead over Masters champion Bubba Watson, with McIlroy falling nine shots behind.
Casey was at 12-under 132.
McIlroy opened with a 63 and was 15 shots worse Friday. He didn't blame a sore left knee as much as his inability to hit fairways. He made three straight double bogeys, had a nine-hole score of 40 or worse in his fourth straight PGA Tour event and had a 78.
Watson got within one shot of Casey late in the round until closing with back-to-back bogeys for a 69.
Jennifer Johnson matched the course record with a nine-under 62 on Friday to take the first-round lead in the ShopRite LPGA Classic.
The 22-year-old Johnson, the winner last year in Mobile, Alabama, had 10 birdies — five straight on Nos. 9-13 — and a bogey on the Bay Course at Stockton Seaview Hotel and Golf Club in Galloway Township, N.J.
The only other players to shoot 62 at Seaview were Laura Davies and Jimin Kang in 2005. Haru Nomura had a bogey-free 63, and Christina Kim opened with a 64.
Top-ranked Inbee Park and Na Yeon Choi shot 66 in the morning session. Park, winless this season, missed the cut last week in Alabama to end her streak at 22 events.
Second-ranked Stacy Lewis and Michelle Wie shot 67, and 17-year-old Lydia Ko was another stroke back.
Spain's Alvaro Quiros shot a five-under 67 Friday to move to the top of the Nordea Masters leaderboard along with Frenchman Victor Dubuisson and Eddie Pepperell of England. All three are six under after two rounds on the PGA Sweden National's Lakes Course in Malmo.
Second-ranked Henrik Stenson birdied the last hole to move to within a shot of the leaders. Fellow Swede and Masters runner-up Jonas Blixt missed the cut after his second consecutive 74.
Several players struggled in the strong winds, including Miguel Angel Jimenez, who shot a 73 on the day for a two under.