Interstate 83 begins its northern trek at Fayette St. in downtown Baltimore, east of the central business district. Originally planned to continue south of Fayette St. to Interstate 95 north of the Fort McHenry Tunnel, the route was truncated in late 1982 and now ends at Fayette St., downgrading into President St. south of the intersection.
North of Fayette St., I-83 is an elevated four- and six-lane freeway, known locally as the Jones Falls Expressway or JFX, that parallels Maryland Route 25 Falls Road and its namesake river, the Jones Falls, which flows directly beneath the freeway. Both I-83 and MD 25 follow a circuitous path out of the city centre, passing beneath US 40 Orleans St with no access and interchanging with Maryland Route 2 and US 1 north of the CBD. Beyond US 1, the JFX is also paralleled by the Baltimore Light Rail system.
After exiting Baltimore, the JFX continues north and eventually reaches Interstate 695, the Baltimore Beltway. I-83 separates from the JFX, which runs beyond the Beltway and terminates at MD 25, and joins I-695 for 1.4 miles; recent construction work widened the concurrency between the two Interstates to ten lanes. I-83 and I-695 split off at the southern terminus of the Baltimore-Harrisburg Expressway, and I-695 continues its eastward trek towards Towson and Parkville.
After separating from the Beltway, I-83 is now known as the Baltimore-Harrisburg Expressway. Running due north away from the Beltway, the route parallels Maryland Route 45 York Road, the former route of US 111. Passing to the west of Timonium and Cockeysville, I-83 leaves the suburban belt around Baltimore and enters rural Baltimore County just north of Hunt Valley at Shawan Road. I-83 and MD 45 continue to parallel one another through the northern portion of the county, with both crossing over each other repeatedly. This segment of I-83 has several sections with higher than usual gradients.
The only major settlement encountered by I-83 along this stretch is Monkton, reached via Maryland Route 137. To the west of I-83, MD 137 connects with the northern terminus of MD 25, I-83's former companion to the south.
The Interstate eventually crosses the Mason-Dixon Line into Pennsylvania 25 miles north of Baltimore, mere feet from a partial interchange with Freeland Road and parallel with MD 45; the latter route becomes the Susquehanna Trail on the other side of the line.
I-83 enters Pennsylvania southeast of New Freedom, passing to the east of Shrewsbury and running due north towards York. The route bypasses the towns of Loganville and Jacobus before entering the city of York.
Uniquely for an Interstate near the east coast, I-83 has a business route through downtown York, known as Interstate 83 Business. The business route follows the former path of US 111, while I-83 turns northeast and then north again to bypass the urban area. Near US 30 Lincoln Highway, the Interstate turns west for a short distance, then north again to interchange with the U.S. route. Beyond US 30, I-83 resumes its straight path, running due north out of York and passing to the west of Emigsville.
North of Pennsylvania Route 295, I-83 is known as the Susquehanna Expressway. It maintains this name as it passes to the south and west of Valley Green, continuing north towards Harrisburg. South of Harrisburg, I-83 interchanges with Interstate 76, the Pennsylvania Turnpike. North of I-76, I-83 continues due north, passing through New Cumberland, before merging with Pennsylvania Route 581 in Lemoyne.
After merging with PA 581, I-83 is known as the Harrisburg Expressway. The highway turns due east within the merge and crosses the Susquehanna River south of Harrisburg's central business district, passing through Paxtang before encountering Interstate 283 and US 322 at the Eisenhower Interchange. Within the interchange, I-83 exits from itself, with each direction of traffic following a one-lane ramp; I-83's former mainline carriageways become US 322, while I-283's former mainline carriageways become I-83. The interchanges includes ramps to local city streets as well. From this point northbound to exit 51 traffic is often congested during daylight hours.
Beyond this interchange, I-83 runs due north again through eastern Harrisburg, interchanging with US 22 northeast of the central business district, before terminating at a three-way semi-directional interchange with Interstate 81.