Dua Lipa demanded a pay rise for NHS workers as she won two major awards at the Brits - the UK's first major in-person ceremony of the Covid era.
And Little Mix called out sexism in the music industry after becoming the first all-female outfit to win best British group.
The other big winners on the night were J Hus, Harry Styles and Taylor Swift.
The test event at London's O2 Arena took place with a 4,000-strong audience and no social distancing or face masks.
Rappers Headie One and AJ Tracey used several verses of their performance to call out the demonisation of drill music and criticise the government, while highlighting the work done by footballer and free school meals campaigner Marcus Rashford.
While the 2021 Brits were not on a leap year it was very much a Lipa year, as the singer won two of the three awards for which she was nominated.
Future Nostalgia, the best-selling album released last year in the UK, predictably won best album.
But it was after winning the best British female award, her first of the night, that the star called on Prime Minister Boris Johnson to give nurses and NHS workers pay rises, as opposed to mere applause.
This year, each of the Brit award trophies came in two parts and Dua dedicated hers to British nurse Dame Elizabeth Anionwu - who she noted has spent "a stellar nursing career fighting racial injustice" and "protecting frontline workers".
"She has also said that there's a massive disparity between gratitude and respect for frontline workers," said the singer. "Because it's very good to clap for them, but we need to pay them.
"So I think what we should do, is we should all give a massive, massive round of applause and give Boris a message that we all support a fair pay rise is for our frontline."
The audience, which was packed with key workers, gave her a standing ovation.
Speaking on BBC Breakfast on Wednesday, environment secretary George Eustice responded to Dua Lipa's speech by stressing there was a "difficult public finance environment".
"There's been a pay freeze for most of the public sector and it's also important to recognise that in recent years that there have been some pay rises as well, particularly for nurses and the lower paid," he said.
"We can't always go as far as you'd like, but it's also the case that there's a pay review that's going on into the NHS," he continued.
The government recommended in March that NHS staff in England should receive a 1% pay increase this year, while many other public sector workers will have their pay frozen.
Before her double win, Dua Lipa had performed a medley of hits from her latest floor-filling record.
It was a visual love letter to her home city of London, complete with a Tube platform string quartet and a union jack skirt which evoked memories of Spice Girl Geri Halliwell's famous patriotic dress.
'Misogyny and sexism'
The night's big winner also shared her delight at seeing more women on both the stage and the winners' podium - several years after she called out the Brits for overlooking female artists.
This year, by contrast, women won four of the five mixed categories.
One such example, Little Mix dedicated their award to some of the great all-female bands who could and should have won in previous years.
"It's not easy, being a female in the UK pop industry," said Leigh-Anne Pinnock while accepting their award.
"We've seen white male dominance, misogyny and sexism, and a lack of diversity.
"We're proud that we've stuck together, surrounded ourselves with strong women and are now using our voices more than ever."
"The fact that a girl band has never won this award really does speak volumes," added bandmate Jade Thirlwall. "So this award isn't just for us, it's for the Spice Girls, Sugababes, All Saints, Girls Aloud.
"All of the incredible female bands - this one's for you."
Since the departure of Jesy Nelson, Little Mix are now a three-piece. Two of them - Pinnock and Perrie Edwards - have recently announced that they are pregnant.
Speaking to the BBC the day after Little Mix's speech, former Girls Aloud member Nicola Roberts said: "They absolutely deserved that award last night and it's long overdue. I feel very proud of the girls because obviously they've been going for 10 years and it's not too dissimilar from the story of Girls Aloud."
She told 5 Live's Nihal Arthanayake: "We were nominated a good few times for that award but we never received it, it was always a male indie band that would be recognised."
Elsewhere, rapper J Hus was not on hand on the night to pick up his award for best male solo star.
But Harry Styles was - in typically well-tailored fashion, sporting a brown and white Gucci suit - to collect best British single for his ubiquitous hit Watermelon Sugar.
If last month's Oscars took place in tinsel town then the Brits was very much tonsil town, as spectators underwent Covid tests on their way into the event.
The event formed part the government's pilot scheme for reopening live events safely, which includes the forthcoming FA Cup Final.
The live audience of about 4,000 people was about one-fifth of the O2's capacity and more than half of the ticket-holders were key workers from Greater London and their guests.
Several performances were pre-recorded including Coldplay's show opener from a pontoon on the River Thames, and another from best international male The Weeknd.
After being introduced by Jackie Weaver - of local council Zoom meeting fame - Chris Martin and co played their new single Higher Power with a little help from some holograms and pyrotechnics.
Sir Elton John later appeared on tape too alongside Years & Years star Olly Alexander for a rendition of Pet Shop Boys track It's a Sin, title track of the latter's recent drama series.
Before the event, US pop star Taylor Swift - who best international group-winners Haim described as "the most incredible human being" - was announced as the first female winner of the global icon award.
Swift, who normally resides in Los Angeles, was there in-person to accept it and also praised the "help and support we got from the NHS" over the past year.
In the only other award announced beforehand, young singer Griff was named as the winner of the rising star prize, and she demonstrated why with a career-making performance.
Previous winners of the award include Adele, who went on to win a host of more senior Brit Awards in the years that followed.
Another star in bloom, Arlo Parks, said it was "a dream come true" to win the breakthrough award and she sang - in front of a garden centre's worth of sunflowers - like she had been doing it forever.
The event finished with a collaboration between Rag 'n' Bone Man, a virtual Pink, and the Lewisham and Greenwich NHS Trust Choir.
Before teeing them up, comedian Jack Whitehall, hosting the awards for a fourth time, gave "a massive big up to the key workers here tonight, and across the country".
"We will never be able to thank you guys enough," he said.
The 2021 Brit Awards winners in full:
Breakthrough Artist: Arlo Parks
Best British Single: Harry Styles, Watermelon Sugar
Female Solo Artist: Dua Lipa
Male Solo Artist: J Hus
International Female: Billie Eilish
International Male: The Weeknd
International Group: Haim
British Group : Little Mix
Best Album: Dua Lipa, Future Nostalgia
Rising Star: Griff
Global Icon: Taylor Swift