Unions in Greece and Italy also planned work stoppages and demonstrations on a "European Day of Action and Solidarity" against austerity policies, which labour leaders blame for prolonging and worsening the continent's economic crisis.
The international coordination shows "we are looking at a historic moment in the European Union movement," said Fernando Toxo, head of Spain's biggest union, Comisiones Obreras.
Spain, where one in four workers is unemployed, is now teetering on the brink of calling for a European bailout, with Prime Minister Mariano Rajoy trying to put off a rescue that could require even more EU-mandated budget cuts.
Passion has been further inflamed since last week when a Spanish woman jumped from her apartment to her death as bailiffs tried to evict her when her bank foreclosed on a loan. Spaniards are furious at banks being rescued with public cash while ordinary people suffer.
"We're going to protest because they're ignoring people's rights. People are being evicted and they're raising our taxes," said Sandra Gonzalez, 19, a social work student at Madrid's Complutense University who plans to march with friends.
In Portugal, which accepted an EU bailout last year, the streets have been quieter so far but public and political opposition to austerity is mounting, threatening to derail new measures sought by Prime Minister Pedro Passos Coelho. His policies were held up this week as a model by Germany's Angela Merkel, a hate figure in crisis-hit southern European countries.
"The first ever Iberian strike" would be "a great signal of discontent and also a warning to European authorities," said Armenio Carlos, head of Portugal's CGTP union which is organising the action there.
Some 5 million people, or 22 percent of the workforce, are union members in Spain. In Portugal about one fourth of the 5.5 million strong workforce is unionised. Unions have planned rallies and marches in cities throughout both countries, with a major demonstration beginning at 6:30 p.m. (1730 GMT) in Madrid.
Just 20% of Spain's long-distance trains and a third of its commuter trains are expected to run. Lisbon's Metro will be shut completely and only 10 percent of all trains will run under court-ordered minimum service.
More than 600 flights were cancelled in Spain, mainly by Iberia and budget carrier Vueling. Portugal flag carrier TAP cancelled roughly 45 percent of flights.
Hospitals in Spain will fully staff emergency and surgery rooms but non-essential care will be scaled back.
Italy's biggest union, CGIL, called for a work stoppage for several hours across the country. The transportation ministry expects trains and ferries to halt for four hours. Students and teachers are expected to march.
In Greece, which saw a big two-day strike last week while parliament voted on new cuts, the main public and private sector labour unions called for a three-hour work stoppage and an anti-austerity rally in solidarity with the Spaniards and Portuguese.
Athens police expect 10,000 demonstrators, small by the standard of protests there.
Economies shrinking
This will be the first time Spanish unions have held two general strikes in one year. Spain's last general strike, in March, brought factories and ports to a standstill and ignited flashes of street violence.
Protests against cuts and economic reforms have since gained even more steam. A violent march in Madrid in September - coupled with riots in Greece - sparked a Sept. 26 sell-off in the euro and European and U.S. stock markets.
Spain's economy, the euro zone's fourth biggest, will shrink by some 1.5 percent this year, four years after the crash of a decade-long building boom left airports, highways and high-rise buildings disused across the country. Portugal's economy is expected to contract by 3 percent.
Every week seems to bring fresh job cuts. Spain's flagship airline Iberia, owned by UK-based International Airlines Group , said last week it will cut 4,500 jobs. The prestigious El Pais newspaper just laid off almost a quarter of its staff.
Portugal has long avoided the street unrest seen in Spain and Greece, but that appears to be changing as the government continues to seek new measures to shrink a budget deficit. A strike organised by CGTP in March had little impact, but in September hundreds of thousands of Portuguese rallied against a government plan to raise workers' social security contributions.
"This austerity is a never-ending story. We see no light at the end of the end of the tunnel, just more pain and difficulties. We have to protest, do something to stop it," said Lisbon pensioner Jose Marques, who plans to march on Wednesday.
