left|thumb|300px|Grand River Avenue sign in East Lansing

M-50 also joined the freeway at Cascade Road headed east, and together I-96/US 16/M-50 continued through eastern Kent County. M-50 departed to the south near Lowell, and the freeway crossed into southern Ionia County. Passing south of Portland, the freeway crossed east into Clinton County. North of Grand Ledge, I-96 ended and US 16 followed Wright Road off the freeway to Grand River Avenue. From there east, US 16 resumed its historic routing into the city of Lansing. Grand River Avenue carried the highway past the Capital City Airport and east to Larch Street, where US 16 turned south along US 27 north of downtown Lansing. At Saginaw Street, eastbound US 16 turned east on the one-way street, while westbound traffic ran a block north on Grand River Avenue. The two directions of travel merge at the east end of Saginaw Street in East Lansing. Grand River Avenue through East Lansing follows a tree-lined boulevard that forms the division between the campus of Michigan State University to the south and the rest of the city to the north. US 16 continued east in Ingham County through Okemos and rural parts of the county through Williamston and Webberville. This street plan was devised by Augustus Woodward and others following a devastating fire in Detroit. A ten-year project to construct a plank road between Detroit and Howell was authorized in 1820 along the Grand River Trail. The Grand River Road, precursor to the modern Grand River Avenue was named by Benjamin Williams, cofounder of Owosso. The original Native American name for the river was meaning "the river that extends far off", or "far into the interior", which was translated as , the French name for the river; this name was then applied to the name of the trail that paralleled at least half of the river's length.

The opening of the Erie Canal in New York in 1826 brought new settlers to the Great Lakes region, and to the future state of Michigan. Many of these settlers began their inland journeys in Detroit. At first the Grand River Road was a "deep rutted, ditch bordered road". The road branched into two at Rouge (now Redford); the southern branch roughly followed the modern route of Grand River Avenue and the northern route ran by way of Pontiac along Woodward Avenue and the modern M-21 to the north of the Lansing area. From Bancroft, several trails branched off, including the northern branch of the Grand River Road and the Saginaw Trail. The two branches merged back together near Dewitt and continued west toward Ionia and on to Grand Rapids and Newton (now Grand Haven). The early travelers plied the road in wagons pulled by oxen or horses, and drivers charged between four and seven cents a mile (equivalent to $–/mi in ).<!--This is set up so that the two inflation adjustments will always adjust to the same year, even when they have different series end years.--> The horses were exchanged every with the speed averaging around with few obstacles.

Congress further aided the road in 1835 with an appropriation of $25,000 (equivalent to $ in ) for a road on of right-of-way. These improvements included removing brush and debris and the construction of bridges across the Rouge, Shiawassee, Red Cedar and Grand rivers. The Grand River Road was a major route for settlers headed inland to Grand Rapids in 1836, as the shortest route for travelers coming from Detroit. An economic panic in 1837 drove settlers from New York to Michigan; these were the travelers who followed the Grand River Road. New settlements were created along the route, every or so, that distance being a good day's travel by horse. Approximately 120&nbsp;wagons left Detroit each day between August and November 1843. When the state capital was moved to Lansing in 1847, an improved road was needed to the capital city. The first segments of roadway were privatized starting in 1844. which set about converting various Indian trails into the Lansing–Howell Plank Road, a task the company completed by 1853. At Howell the road connected with the Detroit–Howell Plank Road, establishing the first improved connection direct from the state capital to Michigan's largest metropolis. The Lansing–Detroit Plank Road was a toll road until the 1880s, and it eventually evolved into the eastern part of the modern Grand River Avenue.

thumb|left|300px|West Grand River Avenue in Howell, 1900

By 1900, only a short stretch of the Detroit–Howell Plank Road was still made of planks; most of the other plank roads had been converted to gravel by this time. On May 13, 1913, the Michigan Legislature passed the State Reward Trunk Line Highway Act (Public Act 334 of 1913) that created the original state highway system. In that act, Grand River Avenue between Detroit and Grand Rapids was included as Division&nbsp;9 of the system. The state highways were signposted starting in 1919, and on the first maps published on July 1 of that year, the Michigan State Highway Department (MSHD) had applied the M-16 number to Grand River Avenue across the state between Grand Haven and Detroit. M-16 was rerouted in the Lansing area in 1925, running along Grand River Avenue from Grand Ledge to East Lansing. The former routing through Downtown Lansing on Michigan Avenue became part of M-39 and the section north of Grand Ledge was eventually redesignated M-100. A second realignment moved M-16 to follow Grand River Avenue from Ionia through Ada. The former alignment became a part of M-21. On August 7, 1926, the state completed paving on M-16, opening it to traffic as "the first paved highway across the state".

The M-16 designation lasted for seven years. As the states were meeting with the American Association of State Highway Officials (AASHO, now AASHTO) to plan the United States Numbered Highway System, the route of M-16 was originally planned for inclusion in US&nbsp;18. When the system was created on November 11, 1926,

US Highway to Interstate

Business US Highway&nbsp;16 (Bus. US&nbsp;16) was a business loop through downtown Farmington along Grand River Avenue. Its western terminus was at the junction of US&nbsp;16 and Grand River Avenue west of the city, and the eastern terminus was at the intersection between US&nbsp;16 and Grand River Avenue southeast of Farmington. This highway was the original route of US&nbsp;16 through downtown Farmington. In 1933, US&nbsp;16 was routed onto a bypass route which had been constructed south of the city (the present-day Freedom Road) and the route through Farmington was retained as state trunkline. and the business route was redesignated as Business Loop I-96 two years later.