[11] Before his sophomore season, James was ranked as the third-best second year player, behind only Josh Rosen and Calvin Ridley, by Lance Zierlein.

[12] On September 13, 2016, it was revealed that James would undergo knee surgery to repair a lateral meniscus tear and cartilage damage.

[16] On December 5, 2017, James released a statement through his Instagram account that announced his decision to forgo his remaining eligibility and enter the 2018 NFL Draft.

His combine performance impressed scouts and draft experts as he finished third among all defensive backs in the bench press and ninth among all safeties in the 40-yard dash.

[23][24] NFL analyst Mel Kiper Jr. ranked him as the top safety in the draft and fourth overall prospect in his big board.

[30][31] James entered training camp slated as the starting strong safety, but suffered a hamstring injury that limited his progress.

[34] On September 9, 2018, James made his professional regular season debut and first career start in the Los Angeles Chargers' home-opener against the Kansas City Chiefs and recorded three combined tackles (two solo), broke up two passes, and made his first career sack on quarterback Patrick Mahomes during a 38–28 loss.

[43] Throughout training camp, defensive coordinator Gus Bradley held an open competition between James, Rayshawn Jenkins, and rookie Nasir Adderley to name the starting free safety after Jahleel Addae was released during the off-season.

[44] On August 15, 2019, it was revealed that James had been dealing with a stress fracture in his right foot that would require surgery and would take up to three months to recover.

On September 5, 2020, the Los Angeles Chargers officially placed James on season-ending injured reserve after he underwent surgery to repair a torn meniscus.

[54]On January 4, 2021, the Los Angeles Chargers officially fired head coach Anthony Lynn after they finished the 2020 NFL season with a 7–9 record.

[56] On April 30, 2021, the Los Angeles Chargers exercised the fifth-year option on James' rookie contract which guarantees a salary of $9.05 million for the 2022 NFL season.

[60] He finished the season with a total of 118 combined tackles (75 solo), five pass deflections, three forced fumbles, two sacks, and two interceptions in 14 games and 14 starts.

[70] On December 26, 2022, James had three combined tackles (one solo) and intercepted a pass by Nick Foles before being ejected in the fourth quarter of a 20–3 win at the Indianapolis Colts after delivering an illegal helmet-to-helmet hit on wide receiver Ashton Dulin.

[71] He finished the 2022 NFL season with a total of 115 combined tackles (64 solo),four sacks, two interceptions, six passes defended, and two forced fumbles in 14 games and 14 starts.

He earned a coverage grade of 74.5 from PFF [43] He returned as the de facto starting strong safety in 2023, but was paired with Alohi Gilman following the retirement of Nasir Adderley.

[75] In Week 17, James recorded 12 combined tackles (seven solo), tied his season-high of two pass break ups, and had one sack as the Chargers lost 9–16 at the Denver Broncos.

He finished the 2023 NFL season with a total of 125 combined tackles (86 solo), seven passes defended, two sacks, two fumble recoveries, and one interception in 16 games and 16 starts.

[79] Defensive coordinator Jesse Minter retained James and Alohi Gilman as the starting safeties to begin the season.

[80] In Week 11, James produced a season-high ten combined tackles and was credited with half a sack during a 34–27 win against the Cincinnati Bengals.