[citation needed] The western segment of SR 78 proceeds east-northeast through Cape Coral and North Fort Myers, where it intersects U.S. Route 41.

SR 78 becomes Bayshore Road in North Fort Myers at its intersection with U.S. Route 41 Business (which is part of an earlier alignment of US 41 and the Tamiami Trail).

Bayshore Road continues east paralleling the north shore of the Caloosahatchee River.

It intersects with Interstate 75 shortly before terminating at SR 31 near the Lee County Civic Center.

The central section of SR 78 is entirely within a part of Glades County dedicated to the growth of foliage house plants.

Motorists driving “east” (actually north) on SR 78, travel through Sportsman Village before visiting the Brighton Seminole Indian Reservation and Buckhead Ridge before reaching the northern (“eastern”) terminus, an intersection with US 98 (SR 700)-US 441 (SR 15) near Eagle Bay in the northern tip of Lake Okeechobee, roughly three miles to the south of Okeechobee.

[3][4][5] Some of these state roads were previously cattle trails and ox-wagon routes that dated back to the American Civil War.

[8][6] In April 1959, SR 78 was realigned from Daughtry Creek to the Atlantic Coast Line Railroad crossing in North Fort Myers.

It provides a quicker way for motorists traveling east on CR 78 to access Downtown Fort Myers.