The move is reported to be worth around €30m including bonuses, and sees the 25-year-old Spaniard step in as the long-term replacement for Alejandro Grimaldo, who left Bayer Leverkusen for Atletico Madrid earlier this summer for €22m after three standout seasons at the BayArena.
Sporting director Simon Rolfes described Gutierrez as "a skilful, offensively oriented defender who fits well with our team," adding: "With him we've brought in a new, highly energising element for our Werkself."
Gutierrez only arrived in Naples a year ago, joining from Girona for €18m and making 36 appearances for the club, contributing one goal and one assist as Napoli finished the season as Serie A runners-up. His departure means a quick reversal for the Italian club, who will nonetheless make a profit on the deal inside just twelve months.
The defender, capped at senior level for Spain, spent time in Real Madrid's youth system before his move to Girona, where he made over 100 appearances and established himself as one of LaLiga's more highly regarded young full-backs.
"The club has made a big impression on me over the past few years - Bayer 04 has an excellent reputation in Italy and also in my home country of Spain," Gutierrez said.
"I've heard a lot about the Bundesliga, watched some games, and I'm really looking forward to the atmosphere in German stadiums.
"Above all, I always want to be successful, both nationally and internationally, and Bayer Leverkusen, with a great team, gives me the best conditions to do that."
The signing continues Leverkusen's pattern of moving quickly to replace departing first-team regulars with players of a similar profile, having lost Grimaldo to Atletico Madrid only weeks earlier following three seasons in which the Spaniard became one of the Bundesliga's most productive attacking full-backs.
Gutierrez, comfortable both defensively and as an auxiliary attacker down the left flank, is expected to slot into a similar role under head coach Carles Martinez, giving Leverkusen a like-for-like replacement rather than requiring a significant tactical rethink.
Napoli's decision to sanction the sale so soon after signing him reflects the financial realities facing the Serie A runners-up this summer, with the Italian club needing to balance their books following a busy period of recruitment of their own.