Lyles completed a sprint treble by winning gold medals in the 100-meter, 200-meter and 4x100-meter events at the 2023 World Championships.

In November 2015, he was named 2015 high school boys athlete of the year by Track & Field News.

[5][28] In November 2016, Lyles was again named high school boys athlete of the year for 2016 by Track & Field News.

Lyles started 2017 with his first senior national title in the 300 m at the 2017 USA Indoor Championships in the thin air of Albuquerque, New Mexico, improving the indoor world record by one hundredth of a second to 31.87 s.[29][30] He earned a silver medal in the 4 × 200-meter relay with team USA at the 2017 World Relays.

Lyles returned to Albuquerque to compete at the 2018 USA Indoor Championships, but in the 60-meter dash instead of the 300 m. He made it through his first heat while equaling his personal best time of 6.57 s, but failed to advance through his semi-final.

Having failed to make the national team for the 2018 World Indoor Championships, he turned his focus to preparing for the outdoor season.

Mike Rodgers had set the world lead a day before in a separate heat, but he did not start in the semi-finals.

This left Lyles' primary rival to be Ronnie Baker, who had run the 100 m in 9.78 s at the Prefontaine Classic earlier that year, but with a wind velocity just over the allowable limit for record purposes (+2.4 m/s).

[37][38] Before that Lyles equaled his personal best and world lead at the Athletissima IAAF Diamond League meet to win a greatly anticipated showdown against Michael Norman, who had set the indoor world record in the 400-meter dash earlier that year.

[41] The two were placed in adjacent lanes and ran evenly through the bend, but Lyles started to pull away on the straight and finished in 19.67 s.[42] It was his fourth time under 19.70 s in the same season.

A month later at Athletissima in Lausanne, he dropped his personal best to 19.50 (−0.1) to move into the number four position on the all time list.

With the extended schedule in 2019, he ran the US National Championships at the end of July, taking the 200-meter title in 19.78 (−0.7) into a headwind in Des Moines.

Lyles won gold medals in the 200 m and the 4 × 100 m relay at the 2019 World Athletics Championships held in Doha, Qatar.

[45] On July 21, 2022, during the World Athletics Championships on home soil in Eugene, Oregon, Lyles claimed his second global title in the 200 m and surpassed Michael Johnson's long standing national record of 19.32 by running 19.31, which moved him to third on the world all-time list.

Lyles was undefeated in his specialist event that year, breaking 20 seconds in all 12 of his races, including heats and finals.