Memorial Highway ends at the interchange with I-275, but SR 60 turns east along John F. Kennedy Boulevard (originally Grand Central Avenue), thus becoming the main non-limited access route from downtown Tampa to Brandon, as it passes WestShore Plaza.

Notable exceptions are sites such as the American Legion Cemetery just before the intersection with U.S. Route 92 at Dale Mabry Highway.

One of the more unique intersections is with Willow Avenue which also has a railroad crossing with the CSX Port Tampa Spur from the southwest to northeast corners.

At Snow Park, Kennedy Boulevard branches off to the northeast while Grand Central Avenue continues straight east.

Originally known as the Lafayette Street Drawbridge, the bridge was added to the National Register of Historic Places on February 20, 2018.

The one-way pair in Tampa ends when eastbound SR 60/45/US Bus 41 turns north onto Meridian Avenue and east onto Kennedy Boulevard.

East of US Bus 41, the route runs under the southern terminus of the Interstate 4 Connector with no connecting ramps, then has a major intersection with US 41 (50th Street) followed by driveways to the CSX Uceta Yard.

The industrial development continues as the road runs along a bridge over the Tampa Bypass Canal then intersects South 78th Street (CR 573), which includes part of another interchange with Lee Roy Selmon Expressway on the southeast corner.

The zoning gradually transitions from industrial to mainstream commercial, most notably at the northwest entrance to the Brandon Town Center.

Following the weigh station, SR 60 encounters a railroad crossing with the CSX Plant City Subdivision.

The route begins curving to the southeast as it enters Bealsville then turns east again as it crosses the wetlands of the English River, and shortly after it intersects South County Line Road at the Hillsborough-Polk County Line only to return to the southeast as it approaches the South Lakeland Airstrip.

The name Canal Street terminates at Kid Ellis Road and SR 60 resumes signage east of Mulberry.

The road takes a brief northeast bend after it approaches a railroad crossing with a spur leading to some phosphate mines owned by Mosaic.

East of these two structures, the road edges at a southeast angle where the presence of construction and chemical companies begins to diminish (though not necessarily disappear) as it approaches the second crossing of the Valrico Subdivision.

The transition from West to East Van Fleet Drive occurs when SR 60 encounters the intersection with U.S. Route 98 in Florida (Broadway Avenue and hidden SRs 35 and 700).

An intersection that would otherwise be unimportant is Enterprise Boulevard, a small road leading to the Polk State College - Clear Springs Advanced Technology Center.

Attempting to move to the northeast one last time before turning back southeast, the landscape is slightly more developed, and it encounters the road to Lake Wales Municipal Airport.

SR 60 leaves West Polk Avenue and moves southeast onto Hesperides Road in eastern Lake Wales.

Still rural, the route enters Yeehaw Junction where it encounters US 441 and the historic site of the former Desert Inn and Restaurant, until it was destroyed by a jackknifing tractor-trailer in 2019.

East of US 441, the road is upgraded again at the interchange Florida's Turnpike and resumes its status as a four-lane divided highway.

Entering the county, the road briefly turns east then southeast again after the north gate of Wedgworth Farms, only to turn east again at the Fort Drum Marsh, where it runs between the Blue Cypress Conservation Area[10] and Fort Drum Wildlife Management Area.

It is at 43rd Street east of the bridge over the Main Canal where SR 60 officially enters the City of Vero Beach.

The two streets run parallel to each other through the railroad crossing of the Florida East Coast Railway Main Line.

The route leaves Indian River Boulevard to turn east again at the road leading to the Merrill P. Barber Bridge.