The FW43B's existence was a direct consequence of the global pandemic. Under an agreement between the FIA and Formula One teams, the planned 2021 technical regulation overhaul was postponed to 2022, forcing teams to carry over and develop their 2020 cars. Williams had introduced the original FW43 for 2020, a car designed by David Worner and Jonathan Carter that produced zero championship points across the entire season — the team's first pointless campaign since 1976. The B-spec update introduced a revised livery paying homage to the team's historic success and to founder Sir Frank Williams, who had departed the team following the 2020 Italian Grand Prix after the sale of the team to Dorilton Capital.
The FW43B made its competitive debut at the 2021 Bahrain Grand Prix. George Russell quickly demonstrated that the car was a genuine step forward, consistently challenging for top-ten qualifying positions and threatening points finishes throughout the year. Williams' first points of the season arrived at the Hungarian Grand Prix, where Latifi and Russell finished 8th and 9th on the road respectively; both were subsequently promoted one place following Sebastian Vettel's disqualification from second, delivering 10 points and lifting Williams above Haas and Alfa Romeo to eighth in the Constructors' Championship.
The most dramatic moment of the FW43B's campaign came at the Belgian Grand Prix, where Russell qualified second on the grid after a brilliant final lap in a chaotic wet session. The race itself was highly controversial — after a long delay it ran for just three laps under the safety car before being red-flagged and declared, with results taken from the formation laps. Russell was classified second, earning Williams their first podium finish since the 2017 Azerbaijan Grand Prix and doubling the team's points tally to 20 (half points were awarded). Latifi, benefiting from pre-race penalties to others, was classified ninth.
Three races later at the Russian Grand Prix, Russell again exploited wet conditions to qualify third. He finished tenth in the race, scoring the final point of his Williams career before his move to Mercedes for 2022.
The FW43B's livery incorporated blue, white, and yellow tones that referenced Williams' iconic championship-winning heritage. The car was the last to carry the Ayrton Senna tribute logo on the front wing, a feature that had appeared on every Williams car since 1995.
The team used the halo device to carry tributes throughout the season. At Bahrain, the halo bore the words of legendary commentator Murray Walker — "And I've got to stop, because I've got a lump in my throat" — following his death the week before the race. At Monaco, the halo displayed the names of 100 fans to mark the team's 750th Grand Prix. At the Saudi Arabian Grand Prix, a week after Sir Frank Williams passed away, the team ran the historic Frank Williams Racing Cars logo behind the sidepods alongside the Top Gun quote "I feel the need, the need for speed" on the halo.
George Russell drove the FW43B for the entirety of 2021 in what proved to be his final season at Williams. Nicholas Latifi continued as his team-mate. Roy Nissany handled the first two days of pre-season testing and also participated in the first practice session at the Spanish Grand Prix as part of his test driver duties.
The FW43B represented a genuine competitive recovery for Williams after the nadir of 2020. The Belgian podium — however controversial the race result — was a landmark result for a team that had been at the back of the grid for several seasons. The car's 2021 campaign closed the chapter on the Williams family's direct involvement in the team and marked the end of Russell's tenure, paving the way for his move to Mercedes where he would go on to win races and challenge for the World Championship.