Network Rail said the railway station would be shut between 30 September and 22 October so passenger capacity can be increased.
It is part of the rail management company and Liverpool City Region's Â£340m project to upgrade 10 railways.
A spokesman for Network Rail said disruption would be "kept to a minimum" and most services would run to and from Liverpool South Parkway instead.
Annual passenger numbers at Lime Street station are forecast to double in peak periods by 2043, said Network Rail, and these improvements will enable it to cater for the increased capacity.
The work will see two new platforms created, existing platforms remodelled, overhead line equipment to power electric trains installed and tracks upgraded.
The six train companies which serve Liverpool have been working on a plan for more than a year to keep customers moving.
Network Rail said bus replacement services would be offered when necessary and passengers would be guided to alternative city centre stations.
The company's spokesman said the renovation was "the biggest upgrade of the station since the 19th Century".
"It will provide passengers with faster, more frequent and reliable train services by 2019," he added.
Liverpool Lime Street was closed for a week for emergency repair work after a wall collapsed on to the tracks on 28 February.
The work is not related to the damage caused by 200 tonnes of debris which fell on tracks in the approach to the station, said Network Rail.
Source Network Rail
Liverpool Lime Street is to close for three weeks for a major refurbishment.