Last-minute talks between unions and rail bosses are continuing, but industrial action is expected to take place on most major lines on Tuesday, Thursday and Saturday.
Network Rail says the last trains between many major cities are expected to depart over the course of this afternoon, Monday, before more than 40,000 rail workers walk out over job cuts, pay and conditions. The strike is due to begin at 00:01 BST on Tuesday.
A reduced timetable will be in place until Sunday, with just 20 per cent of usual services running on strike days.
Trains that do run will start later and finish much earlier than usual - between 7.30am and 6.30pm.
Knock-on disruption is expected on the roads, with motorists being warned to expected a surge in traffic.
The RAC has said that major city routes and those serving the home counties are likely to see some of the biggest increases in traffic volumes.
The strikes will also affect a number of events including school exams and the first Glastonbury Festival to take place for three years.
Trains operated by Avanti West Coast, Northern Trains and TransPennine Express - which all use the lines through Lancaster, Morecambe, Carnforth and beyond - are among those to be affected, and they have urged travellers to make alternative arrangements where possible.
Avanti West Coast said: "Due to strike action by the RMT union, we’ll be operating a significantly reduced timetable on Tuesday 21 June, Thursday 23 June and Saturday 25 June. This means fewer trains will run and some stations and destinations will have no service on the strike days. Our services will also start later and end much earlier.
"These trains are expected to be very busy, so we strongly advise to only travel by rail if necessary on strike days. If not, please plan ahead as your journey will probably be severely disrupted. Train travel on days either side of the strike days is also likely to be affected.
"If you have tickets for travel from Tuesday 21 June to Sunday 26 June, you can use those tickets any time between now and Monday 27 June. Alternatively, you can claim a full refund if you have tickets for travel on Tuesday 21 June to Sunday 26 June.
"To help reduce disruption and overcrowding, we’re suspending sales of tickets for the three strike dates (21, 23 and 25 June), and for the days after industrial action (22, 24 and 26 June). Once each day's timetable is confirmed and we know which trains are running, some Advance fares will be back on sale.
"Please keep checking our website, and those of other operators, for the latest updates. We will of course do all we can to keep you informed."
Northern Trains said: "Customer safety is our priority, we advise you not to travel between Tuesday 21 and Sunday 26 June and make alternative plans.
"On strike days there will be extremely limited availability of both train crew and signalling staff and as such we will not be able to operate services on most routes. There will be no replacement buses or alternative travel provided.
"Unfortunately, as we will not be able to position our fleet how we normally would, the significant impact of the strike will also be felt on non-strike days. Therefore, we regrettably advise customers not to travel on any day from Tuesday 21st through to Sunday 26th June.
"Where we are able to operate trains, services will be very limited, and trains will not start as early as normal and will finish much earlier than normal.
"You will be entitled to a refund for dates affected by strike action if not travelling."
TransPennine Express said: "TransPennine Express is asking customers to plan carefully ahead of planned RMT strike action taking place during this week on Tuesday 21, Thursday 23 and Saturday 25 June.
"An amended timetable will be in place on these dates, which will see a significant reduction in available services. We’re advising customers to only travel if journeys are essential and to seek alternative means of transport if possible.
"There will also be significant disruption on days between strike action (Wednesday 22 and Friday 24 June) and customers are asked to plan carefully and to check timetables before travelling."
The RMT is unhappy about stagnating pay and proposed job losses, and so far talks between the union and Network Rail - which maintains tracks and runs bigger stations - have failed to find a resolution.
TUC (Trades Union Congress) general secretary Frances O'Grady said nobody took strike action lightly but argued rail staff had been left with "no other option".
"Many rail staff who will be hit hardest - such as caterers and cleaners - are on low and average earnings," she said. "It's insulting to ask them to take yet another real-terms pay cut when rail companies took £500 million in profits during the pandemic."
However, Rail Delivery Group chair Steve Montgomery said rail bosses were trying to work with unions "on how to carry out modernisation and reform of the industry" amid falling passenger numbers.