I-29 runs from Kansas City, Missouri, at a junction with I-35 and I-70, to the Canada–US border near Pembina, North Dakota, where it connects with Manitoba Provincial Trunk Highway 75 (PTH 75), which continues on to Winnipeg.

The Interstate diverts from US 71 just north of St. Joseph and follows a sparsely populated corridor along the Missouri River to Council Bluffs.

During the design phase there was an alternative sending the route further along US 71 through the bigger towns of Maryville, Missouri, and Clarinda, Iowa.

After continuing toward downtown Sioux City on a northerly route, I-29 turns west and enters South Dakota.

The portion from Fargo, North Dakota, to the Canada–US border was originally considered for designation as Interstate 31 (I-31) in 1957 for present-day I-29.

In March and April 2019, as a result of the 2019 Midwestern US floods, I-29 was closed in both directions for approximately 187 miles (301 km) between St. Joseph and Council Bluffs.

Much of this section of I-29, including at the Missouri–Iowa border, runs over or through a large floodplain for the Missouri and Platte rivers.

By May 2019, the vast majority of I-29 had been repaired and reopened, with the exception of 10 miles (16 km) around Council Bluffs where the highway ran concurrent with I-680 (now the portion of I-29 between I-680 and I-880).

At a few times, the entire 187-mile (301 km) section between St. Joseph and Council Bluffs was completely shut down, although this was rare after May 2019.

[7][8][9] As of October 2019, all of I-29 is open to traffic in both directions, although some Missouri River bridges and local farm roads remain closed due to flooding.