The highway begins in Yonkers city as Central Park Avenue at Exit 4 of the New York State Thruway (I-87). This portion of Central Park Avenue is maintained by Westchester County with unsigned county road designations CR 47II. Central Park Avenue continues south into the Bronx and serves as a frontage road for I-87 in this area. NY 100 diverges from I-87 just north of Exit 5 and heads northeast, crossing over the Sprain Brook Parkway about 0.6 mile beyond the split. Central Park Avenue continues out of the city of Yonkers in the area between the Grassy Sprain Reservoir and the Bronx River into the town of Greenburgh. NY 100 runs through the hamlet of Hartsdale, about two miles north of the city line, and where the loop route NY 100A (Hartsdale Avenue) begins. Central Park Avenue then enters the city limits of White Plains, where the road ends at NY 119 (Tarrytown Road). Within White Plains, the road is county-maintained with unsigned designations of CR 99 and CR 90.
NY 100 north follows NY 119 west for a 0.5-mile overlap through the town center of Greenburgh. Access to I-287 and the Bronx River Parkway can be made in the vicinity of the 100/119 overlap. NY 100 then splits off to the north using Hillside Avenue and Grasslands Road as it goes around the perimeter of Westchester Community College. At a four-way intersection between Grasslands Road, Knollwood Road, and Bradhurst Avenue, NY 100 meets with the north end of NY 100A (Knollwood Road) and the east end of NY 100C (Grasslands Road). To continue on NY 100, one must turn north onto Bradhurst Avenue. Bradhurst Avenue leads into the hamlet of Hawthorne within the town of Mount Pleasant, crossing under the Sprain Brook Parkway along the way. NY 100 then shifts onto Saw Mill River Road (NY 9A) using a brief section of NY 141 (Broadway). From this junction, Saw Mill River Road (carrying 9A and 100) is a partially controlled-access highway as it continues north alongside the Taconic State Parkway. It has a grade-separated junction with NY 117 (Bedford Road) about north of the 9A/100 merge. 9A and 100 then enter the eastern edge of the village of Briarcliff Manor.
NY 100 then branches off on its own again in Briarcliff Manor, with NY 9A continuing north along the Briarcliff-Peekskill Parkway and NY 100 continuing northeast on the Saw Mill River Road, which roughly follows New York Central's old Putnam Division railroad. Many of the railroad's old stations can still be found along the highway. NY 100 passes through New Castle and meets NY 133 in the hamlet of Millwood, where access to the Taconic State Parkway can also be made. From here, NY 100 then follows the path of the Croton Turnpike (alternatively known in the area as Somerstown Turnpike and also as Saw Mill River Road). The road continues into the town of Yorktown, passing by the hamlet of Kitchawan. NY 100 then crosses the Croton Reservoir on Pines Bridge. After crossing the reservoir, NY 118 splits off to the west on Saw Mill River Road, while NY 100 continues northeast on the Croton Turnpike.
The Croton Turnpike continues into the town of Somers, passing by some of the last remaining rural areas in Westchester County, including Muscoot Farm, a county owned early-1900's interpretive farm. North of the farm NY 100 intersects with NY 35 in the hamlet of Whitehall Corners, where a Pepsi Cola plant is located. In its northern extremes, NY 100 roughly parallels the Croton Reservoir on the north side before meeting up with US 202 in the hamlet of Somers, where it ends opposite the Elephant Hotel.
The middle section of NY 100 uses the Saw Mill River Road, an early colonial road connecting many different hamlets and villages in Westchester County. It follows along the path of various rivers and brooks as it winds its way to the north of the county. The road is now used as parts of several state routes, including NY 9A, NY 100, and NY 118. The section used by NY 100 follows the path of the Pocantico River between the hamlets of Hawthorne and Millwood.
The northernmost section of NY 100 runs along a part of the "Croton Turnpike", an early private toll road that was chartered in 1807. The Croton Turnpike connects the village of Ossining (then called Sing Sing) to the hamlet of Somers via Kitchawan. The road was made free in 1849. The Saw Mill River Road was rerouted to overlap the Croton Turnpike as it navigates around and across the Croton Reservoir, which was constructed between 1837 and 1842.
In December 1934, at the insistence of the Autombile Club of New York, several numbered routes were extended and signed within New York City, with NY 100 being one of these routes. NY 100 was extended south from the Yonkers line in the Bronx along Jerome Avenue to the Grand Concourse. NY 100 crossed into Manhattan via East 149th Street and the 145th Street Bridge. In Manhattan, NY 100 continued south along Lenox Avenue, 110th Street, Fifth Avenue, 96th Street, and Park Avenue, ending at Houston Street (NY 1A). South of Fordham Road, NY 100 was overlapped with NY 22 all the way to Houston Street.
With the opening of the Major Deegan Expressway in 1956, the NY 100 designation was removed from New York City. NY 100 was cut back to the city line again. No major changes have been made to the NY 100 alignment since then. However, as of 2007, NYSDOT recognizes the Cross County Parkway underpass as the official southern terminus of NY 100.