MSC Cruises’ brand new vessel Virtuosa was due to call at the Inverclyde port for nearly 12 hours on Wednesday as part of a seven-day cruise.
It would have been the first cruise ship to call at a Scottish port this year after other planned visits were cancelled
The trip started in Liverpool and is also due to visit Belfast, Southampton and Portland.
Passengers booked to join the cruise in Greenock may now have to travel by road to Liverpool instead.
The Scottish Passenger Agents Association (SPAA) said passengers had been told by MSC Cruises: “Due to the latest Scottish Government Covid restrictions and regulations … we are sorry to inform you that the port call of Greenock has been cancelled.
"No guests are allowed to embark or disembark.
"This decision has been made by the Scottish Government and is out of our control.”
Further MSC Virtuosa cruises booked to call at Greenock over the following two Wednesdays have also been cancelled, the SPAA said.
Among those affected is a 91-year-old woman taking her last family holiday.
Her daughter tweeted: “Absolutely gutted. My wee 91yr old mum's last family holiday no longer possible, should have been on board on 23rd from Greenock.
"She had even packed her ballgown 2 weeks ago!!! Ok for rest of uk tho!!!! This will crush her! Shambolic.”
Shazza tweeted: “I am going on 7/7 from Greenock and now considering rebooking and starting and ending cruise in Liverpool.
"We can travel to England to join a cruise but not start and finish in Scotland.
"These rules are bonkers and make no sense.”
The SPAA said one third of the hundreds of passengers aboard this week’s cruise had been expected to go ashore for excursions from Greenock.
It said three quarters of passengers had received both Covid vaccine jags and been triple tested, with the crew vaccinated and tested.
SPAA president Joanne Dooey said: “We’re now facing the situation where Scottish passengers who joined the cruise in Liverpool are barred from setting foot in their own country.
"The SPAA has been asking for clarity on the situation for this particular cruise ship since last week, and all we have received so far is an indication that cruises may only restart when all of Scotland is in level one.
"Inverclyde is currently in level one.
"The irony is that any of these passengers can get in a car and drive from Southampton to Inverclyde with no testing, border control or vaccinations.
“This cruise route was a lifeline for Scottish travel agents.
"We are utterly devastated.
"As the door to the only international flight closed this week with Portugal being placed on the amber list, this series of domestic cruising was one of the only products left for travel agents to sell.”
Jacqueline Dobson, president of Barrhead Travel, said: “The news today is yet another hammer-blow for the Scottish travel industry, Scottish holidaymakers and for regional tourism partners who were looking forward to welcoming UK guests ashore for excursions.
“Cruises from Greenock have been on sale for months, yet despite urgent calls from the industry, the Scottish Government has provided less than 36 hours’ notice that these sailings cannot go ahead.”
One of the ship’s passengers, Michele Lister, a branch manager of Glen Travel, said Covid precautions aboard “made it safer than walking about on the streets of Glasgow”.
She said: “We are not allowed to go into our own country, which is really disappointing.
“We were just sitting down to lunch and the captain made an announcement that we would not be allowed to disembark in Greenock and we would remain in Liverpool for another night, and we will now be sailing to Southampton tomorrow.”
An MSC Cruises spokesperson said: “In light of recent information received, we are now awaiting further clarification from the relevant authorities in Scotland about the situation for cruising, which regrettably means we have had to cancel our proposed visit to Greenock tomorrow.
"We hope that our calls to Scotland with our special cruises can commence soon considering how much we were looking forward to welcoming our Scottish guests onboard MSC Virtuosa and how we are aware of the important and widespread contribution the cruise industry makes to Scotland.”
A Scottish Government spokesperson said: “We fully understand the impact of the current restrictions on domestic cruises.
“We explained our concerns about the transmission risks posed by cruise vessels in an update to industry on May 24 and confirmed that we would clarify the position in June.
“Following extensive engagement with stakeholders, we have now confirmed that domestic cruises can restart when all of Scotland reaches level one and we have made industry, including the operator, aware of this.
“This decision has been informed by the combination of risks that exists between both cruises and the wider travel context, including the current trajectory of Covid infections and the unknowns around the new Delta variant, in addition to the potential for high risk of uncontained rapid transmission on the cruise.
“Affected passengers should contact the operator for further information regarding their trip.”
Guidance for domestic cruising would be published ahead of Scotland entering level one.
Rob Mason, chairman of marketing organisation Cruise Scotland, said: “The cruise industry is all too aware of the current position in Scotland due to the Covid situation and awaits a Scottish Government decision to lift the ban on domestic cruise operations which involves UK guests sailing from UK ports on UK itineraries.
“There are healthy bookings by operators in anticipation of the go-ahead following a voluntary suspension of operations ahead of government guidance almost 18 months ago.
"While this was the correct decision, the ongoing suspension is taking its toll on the sector, the supply chain it supports and coastal communities.
“Cruise lines have now adopted rigorous new operating protocols to protect passengers, crews and destinations, including onshore excursions, and have been sailing successfully from and to English ports since restarting on May 20."