The first 40-50 miles East of Chicago, covering up to an hour and a half of travel time on Amtrak trains, pass through heavily-industrialized built-up areas, along with old and very poor housing neighborhoods. Continuing due south from the 21st Street (Fort Wayne Junction) interlocking (MP 521.1), the Double Track, Rule 261 (Current-of-traffic), ABS, 70 mph for passenger trains and 50 mph for freights, line passes the CTA Orange Line overhead bridge just south of the flat crossing at MP 521 (on the former Conrail line), bridging over an east-west street (Cermak Road), a northeast-southwest street (Archer Avenue), 23rd Street and 23rd Place, the junction at 23rd Street, where the former Chicago & Western Indiana Line, now used by Metra Orland Park trains and Amtrak's Cardinal, splits off on the west side, after which the UP (ex-C&EI) Canal Street Yard lies along the west side of the tracks, with all these lines bridging over 24th Street, 24th Place and I-55, passing beneath Interstate 90/94 and 26th Street, after which there is a north-south street (Stewart Avenue) on the east side of the ex-PRR tracks, a bridge over an east-west street (28th Street), the south end of some tracks on the east side, and two bridges over east-west streets (28th Place and 29th Street). Near 35th Street, the Chicago White Sox baseball stadium, Comiskey Park lies across the street on the east side of the line, followed by a bridge over 35th Street?, the Comiskey Park parking lots, where the old stadium used to be prior to the mid-1990s, and two bridges over east-west streets (one of which is Pershing Road).
There is a bridge over the Chicago Union east-west line, a connector from the Chicago Union trailing in from the northwest/west, crossovers at CP 518 (MP 518.5), with a bridge over an east-west street at the crossovers and a signal bridge overhead, where the speed limit drops to 40 mph. The former Wabash 47th Street Yard now lies two tracks over on the west side of the line, followed by a bridge over an east-west street, a bridge over 50th Street, a bridge over an east-west street, and the site of the ex-Conrail, ex-PRR 55th Street Yard (MP 516.9) on the east side of the line. At 58th Street (MP 516.5), there was once a wye on the west side with a line connecting over to the erstwhile "Panhandle" line that ran north-south between Archer and Western Avenues, followed by a bridge over a divided east-west street, and four bridges over east-west streets. At MP 516.3, the speed limit falls to 25 mph as far as MP 516.0, for the curve to the southeast that follows, as the line passes a bridge over a north-south street and beneath the CTA "Elevated" line's Ashland branch on its steel viaduct, then over the Dan Ryan Expressway and the CTA line in its median, and rises to 30 mph for the flat crossing with the Metra Rock Island District's line south from La Salle Street, at Englewood (MP 515.8), and a through girder bridge over an east-west street, where the erstwhile Englewood Union Station was on the northeast side of the crossing.