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. He opened with a win in the 200 m at the IAAF Diamond League Doha meet, setting a new personal best with a time of 19.83 s. A few weeks later he ran the less common 150 m at the adidas Boston Games, winning in a personal best time of 14.77 s. He returned to the 200 m at the IAAF Diamond League in Eugene, winning and improving his personal best time to 19.69 s. This time matched the world leading time set by Clarence Munyai earlier that year.