The station is located in the Moabit district, in the Mitte constituency. To the north is Europaplatz and Invalidenstraße, and to the south is Washingtonplatz and the Spree. South of the station is the Spreebogenpark, the Bundeskanzleramt, and the Paul-Löbe-Haus. To the east is the Mitte district and the Humboldthafen.

Berlin Hauptbahnhof is part of the mushroom concept in Berlin, in which the station forms a connecting point for converging and intersecting lines of different modes of public transport.

The station's length is 430 metres (1,411 ft), though some of the platforms are 80 metres (260 ft) long.

Structurally, the entire station complex is a tower station, while operationally it is a crossing station similar to all central stations. The complex consists of several independent operating points:
• Tracks 1 to 8 are underground and are used for regional and intercity services on the Berlin North–South mainline.
• Tracks 9 and 10 are underground and will be used for the future S21 S-Bahn line.
• Tracks 11 to 14 are elevated and are used for regional and intercity services on the Berlin Stadtbahn.
• Tracks 15 and 16 are elevated and are used for S-Bahn services on the Stadtbahn.
• Tracks U1 and U2 are separate from the main station and are used for U-Bahn line U5.

The station building has two platform levels and three connecting and business levels. Compared to Raffles Place MRT station and Taipei main station, it is one of the most densely packed stations. The upper platform level serves the Berlin Stadtbahn and consists of six elevated tracks on four bridge structures, served by three island platforms 10 metres (33 ft) high. The outer bridges carry one track each, while the inner bridges carry two each. The lower platform level serves the Berlin North–South mainline, and consists of eight underground tracks served by four island platforms 15 metres (49 ft 3 in) deep. To the east are two tracks and an island platform serving U-Bahn line U5 (formerly line U55). Further to the east, a similar double track platform is being built as part of the S21 project.

The bridges carrying the Stadtbahn are approximately 680 metres (2,231 ft) long, and span not only the station area, but also the adjacent Humboldthafen. Due to the way the Stadtbahn is aligned, they are curved, and due to the broadening from four to six tracks and the additional platforms, the total width has increased from 39 to 66 metres (128 to 217 ft) wide. The Humboldthafen Bridge spans the Humboldthafen with a span of 60 metres (197 ft). It consists of a bow with steel tubes and pre-stressed concrete beam as upper flange.

The upper platform hall, which runs east–west, is 321 metres (1,053 ft) long and consists of the arched, column-free, glass roof structure, which is supported by the two outer railway overpass structures. In the glass surface, a 2,700 square metres (29,000 sq ft) photovoltaic system with a capacity of 330 kilowatts was integrated. The hall is between 46 and 66 metres (151 and 217 ft) wide and a maximum of 16 metres (52 ft 6 in) high. It consists of three sections, with the western segment 172 metres (564 ft) and the eastern 107 metres (351 ft) long. In between lies the 50 metres (164 ft) wide and 180 metres (591 ft) long north–south roof, whose barrel vaults with the main roof form a flat viaduct. Parallel to the north–south roof, the two "ironing structures" span the main roof of the platform hall and carry the north–south roof. These ironing structures contain 42,000 square metres (450,000 sq ft) of office space.

On the northeastern part of the two diagonally opposite station terraces, the sculpture of Rolling Horse, erected in 2007 by Jürgen Goertz, artificially complements the building and is reminiscent to Lehrter Bahnhof and Lehrter Stadtbahnhof. There are integrated artificial elements, which can be viewed through four portholes.

From the southwestern terrace, it rises the disguised chimney located underneath the Tunnel Tiergarten Spreebogen.

During Cyclone Kyrill, on 18 January 2007, the 8.4-metre (27 ft 7 in) long, 1.35-tonne (2,976 lb) horizontal strut 40 metres (131 ft 3 in) high, crashed from the lattice-like exterior onto a staircase, onto the southwestern part of the building, another strut was torn from the anchorage. These decorative elements had only been hung up and should only hold their own weight. As a remedy, small sheets were placed above the carrier to prevent further carrier dissolution.