They made the 30-minute journey from Victoria in a Twin Otter aircraft and were greeted by thousands of people gathered on Vancouver's waterfront.
The duke and duchess later met refugees at an immigration centre and went to the Kitsilano coastguard station.
It is first time the Cambridges have toured as a family of four, with Prince George and Princess Charlotte.
The royal couple were greeted on the harbourside by Canadian Prime Minister Justin Trudeau, before meeting well-wishers on a walkabout.
He later paid tribute to the royal couple, saying they are "strong advocates" for young people, "whether it's speaking out about cyber bullying, creating more opportunities for young people to lead in their community through sport coaching, or helping children and young people affected by addiction in their families".
He added that they "understand the need to support and encourage the world's youth".
Leaving Victoria for Coal Harbour, in Vancouver, the duke and duchess were given earplugs for the flight because, although it is the easiest way to travel from Victoria to Vancouver, it is also the noisiest.
A royal aide said: "It was very smooth flying. The duke was very interested in the landing and the different conditions they work in. They spent a lot of time looking at the incredible views from both sides of the plane."
Later, the couple met a family who had fled the civil war in Syria, during a visit with Canada's prime minister and his wife to the Immigrant Services Society of British Columbia (ISS).
Canada has resettled 25,000 Syrian refugees between November 2015 and February this year.
They met Alaa Al Mahameed, 36, and wife Yosra, 35, who came to Canada with their daughters, Reemas, three, Reetaj, two, in August.
The duchess crouched to speak to the two young children and then asked their mother for their ages through a translator.
She asked: "Has it been difficult with young children?"
Yosra told her: "We feel safe here. Much more safe."
Prince William spoke to Alaa about the conflict in Syria, asking: "Was there a lot of devastation in your town? How bad was the situation?"
Alaa said he was relieved the children were born outside of Syria, in Jordan, but admitted: "It's been difficult.
"We hope that things would get better and we could return to Syria but unfortunately things have not improved."
The day ended with the duke being hailed "one of the guys" as he met the emergency services with his wife and the Trudeaus.
The duke - a former RAF search and rescue pilot and current air ambulance pilot - shared his experiences with fellow first responders.
Raising questions about "macho culture", he and the duchess went on to inspect the latest technology available to Canadian fire, police and coastguard services.
24 Sept Victoria,  British Columbia: The duke and duchess, accompanied by their children, arrived in Victoria, the capital of British Columbia.
25 Sept Vancouver, British Columbia:  The duke and duchess visited Sheway, the Immigration Services Society of British Columbia - for an event to celebrate young leaders in Canadian arts, music, sport, charity, business, and film, and then visited the Kitsilano coastguard station.
26 Sept Bella Bella and the Great Bear Rainforest, British Columbia: The duke and duchess will travel to the Great Bear Rainforest, visit the Heiltsuk First Nations community and attend a reception hosted by the province of British Columbia at Government House.
27 Sept Kelowna, British Columbia and Whitehorse, Yukon: The royals will tour the Okanagan campus of the University of British Columbia and take part in the BC government's "Taste of British Columbia" festival at Mission Hill Winery before flying to Whitehorse, where they will be greeted by members of the Canadian Rangers.
28 Sept Whitehorse and Carcross, Yukon: William and Catherine will visit the MacBride Museum and meet members of Whitehorse's cultural community before travelling to Carcross, where they will be welcomed by the Carcross/Tagish First Nation.
29 Sept Victoria, British Columbia: The royal couple and their children attend a children's party in the grounds of Government House, which will be attended by military families.
30 Sept Haida Gwaii, British Columbia:  The duke and duchess visit Haida Gwaii, the archipelago on the northern coast of British Columbia, home to the Haida Nation. They will attend the opening of the new Haida Gwaii hospital and care centre. They will join local youths for a fishing expedition on the waters of Hecate Strait.
30 Sept Victoria, British Columbia: The royal couple will visit the Cridge Centre for the Family, which provides services and support for women who have experienced domestic violence. They will then meet families who have received support from the Kelty Mental Health Resource Centre and later youth working with the Sail and Life Training Society. They end their tour with a public official departure ceremony at Victoria Harbour Airport.
The Duke and Duchess of Cambridge have flown by seaplane to Vancouver on the latest leg of an eight-day Canada tour.