Tygers of Pan Tang and John Sloman's Badlands (1980–1982)
Sykes joined Tygers of Pan Tang in 1980 and his first gig with the band was at Reading Festival in front of 60,000 people. He played guitar on the albums Spellbound (1981) and Crazy Nights (1982), as well as participating on two tracks for their 1983 release, The Cage.
In 1982, John Sykes was recruited by former Uriah Heep frontman John Sloman, for his new band Badlands, alongside his future Whitesnake bandmate Neil Murray. Although there was some interest from EMI, the project was to be short-lived however, as Sykes was offered to join Thin Lizzy and there was no management or finance to hold on to him. Badlands had performed live twice only and disbanded shortly after. No music has ever been officially released, although demo tapes and bootlegs of rehearsals do exist. Prior to joining Badlands, Sykes auditioned, unsuccessfully, for Ozzy Osbourne's band following the death of Randy Rhoads. Sykes also auditioned for Ronnie James Dio's new band, Dio, to record on 1983's "Holy Diver" album but was unsuccessful, as Dio instead chose Sweet Savage guitarist, Vivian Campbell.
Thin Lizzy (1982–1983)
At the age of 23, Sykes was asked by Phil Lynott to join Thin Lizzy, filling the spot left by previous guitarist Snowy White. He participated in the recording of the band's final studio album Thunder and Lightning, deemed by many music historians as the pinnacle of their commercial success. He also co-wrote the track "Cold Sweat" with Phil Lynott: "I came in late. They pretty much had the material together [...] We wrote that in the studio." As for the soloing parts:"A lot are me, some are Scott. On some songs, we took one each".
With Sykes on board and his guitar blazing throughout, the band toured the album successfully for almost a year. The live album Life:Live was recorded during this time. Following the tour, Thin Lizzy disbanded.
Sykes joined Phil Lynott for Sweden's "Folk Park Tour", a series of summer outdoor gigs (July–August), in a band dubbed "The Three Musketeers" (as suggested by Lynott himself in the UK press), featuring Phil Lynott (vocals, bass), Brian Downey (drums), John Sykes (lead guitar), Donal Nagle (rhythm guitar) and Mark Stanway(keyboards). Then, Sykes was contacted by Whitesnake's manager, Ossie Hoppe, to secure his services for the following tour, upping his offer every time to the point Sykes could not refuse. However, Sykes wanted his friend Phil's personal blessing: "So I went to Phil and told him [...] His attitude was: I'd never hold you back- I wish you well. He was a real gentleman about it".
David Coverdale hired Sykes to join Whitesnake following the release of Slide It In in 1984. He re-recorded some guitar tracks for the US release: "I basically beefed up the rhythms [...] me and Neil Murray [...] had two days to do some overdubs [...] Micky Moody and Mel Galley had already recorded the album." The new lineup made their tour debut at SFX Center in Dublin on 17 Feb 1984, followed up by more UK dates, rest of Europe, Japan and USA and culminated with the 1985 Rock in Rio festival, where the band played two gigs (11/01 and 19/01).
Sykes was heavily involved in Whitesnake's next project, co-writing 9 out of 11 songs on the band's self-titled album with David Coverdale. They started working on the songs in the spring of 1985 in South of France and, around September, the band headed to Little Mountain Sound Studios in Vancouver to work with producer Mike Stone. Sykes recorded guitar parts, as well as some backing vocal tracks. Towards the end of the 1987 sessions, Coverdale fired progressively the entire band (allegedly because of personality clashes and matters of ego) and brought in Adrian Vandenberg to record the solo on "Here I Go Again". Sykes later stated: “I regret that I never got to play those songs live - and I think fans regret it, too.” 
This was Whitesnake's most successful album, peaking at #2 on the Billboard 200 chart and selling over eight million copies in the United States alone. It contained the hit singles "Still of the Night", "Is This Love", "Give Me All Your Love", and "Here I Go Again" (the last was not a Sykes composition).
In June 2017, British publication Rock Candy featured an exclusive interview with Sykes, where he stated: "At the time, I had a real sense of where I felt Whitesnake should be heading musically [...] I don't believe David had any clue what we should sound like [...] Geffen were keen to get down on record the sort of style that would appeal to American fans. Up to that point, Whitesnake meant nothing in the US".
Blue Murder (1988–1994)
After Coverdale fired the 1987-era band, Sykes went on to form Blue Murder with Vanilla Fudge drummer Carmine Appice and The Firm bassist Tony Franklin. Sykes subsequently stated: "I was anxious to get back into the saddle, do an album my way and then go on tour [...] Yes, I wrote all the songs, but [...] I always tried to present this as a proper band and not a solo project."
After a demo was recorded with Ray Gillen on vocals, A&R executive John Kalodner encouraged Sykes to handle the vocal duties himself.
Their self-titled debut album was produced by a young Bob Rock, but more than that, it is about Sykes's guitar, balancing technique and emotion. 1989's epic "Valley of the kings" found the band serving up their own Egyptian-themed "Kashmir". However, the 1993 follow-up Nothin' but Trouble did not fare as well. After two studio albums and a live recording, Sykes ended the Blue Murder partnership and he began recording and touring under his own name.
In the April 2014 issue of Classic Rock Magazine, Sykes gave an estimate on chances of reforming Blue Murder: "If I wanted to reform Blue Murder, then I could do it at anytime [...] I am moving forward, not looking back. However, I wouldn't totally rule it out at some point further down the line. I love what we did and if the right circumstances appeared, then who knows...it might happen."
Solo career (1994–present)
In the years following Blue Murder, Sykes recorded several solo albums: Out of My Tree (1995), Loveland (1997), 20th Century (1997) and Nuclear Cowboy (2000). A song from 20th Century, "Cautionary Warning", was used in the anime series Black Heaven.
In 2004, the live album Bad Boy Live! was released, covering a number of "greatest hits" from Thin Lizzy, Whitesnake, Blue Murder, and his solo work.
Sykes has made rare guest appearances on the Hughes Turner Project debut album on the track "Heaven's Missing an Angel", and later on keyboardist Derek Sherinian's 2004 solo album "Mythology", playing alongside Zakk Wylde on the track "God of War".
Thin Lizzy reformed (1994–2009)
In 1994, he reformed Thin Lizzy with Scott Gorham, Brian Downey, and Darren Wharton. Sykes, as well as taking on the role of lead guitarist, handled the lead vocals due to the death of Phil Lynott years earlier.
Touring occasionally with Thin Lizzy, a live recording One Night Only was released in 2000.
On 7 July 2009, Sykes announced that he had parted ways with Thin Lizzy, stating that "I feel it's time to get back to playing my own music".
On 7 May 2011 episode of That Metal Show, when asked about a Blue Murder reunion, Carmine Appice said they were "talking." No further details were given. On 26 July, during his taping of "That Metal Show," Sykes announced that he was forming a new band with drummer Mike Portnoy, dubbed ‘Bad Apple’.
On 24 January 2012, Eddie Trunk confirmed that the Sykes/Portnoy project had dissolved, saying: "Obviously bands are like any relationship, some click, some do not. This was simply a case of two different people not only getting to know each other musically but also personally, and the schedule and timing for making this work just fell apart. Mike and the band's bass player, Billy Sheehan, were ready to go, and John simply was not on the same timetable." The next day, Richie Kotzen was announced to have replaced Sykes. On 29 January, Sykes posted on his website: "The project I was putting together with Mike Portnoy didn't work out, and I wish him all the best for the future. I'm continuing to work on my new album, and I look forward to putting out some great new music in 2012."
In February 2013, Sykes announced he was working on his fifth solo album. The release was initially scheduled for early 2015, but failed to meet the deadline due to business issues. Sykes had also had one of his elbows broken in a car accident, but has since fully recovered.
In early March 2017, Germany's "Rocks" magazine reported that the new album was titled Sy-Ops and scheduled for release before end of 2017. Sykes elaborated on the news in an extensive interview with Japanese magazine Young Guitar published in April 2017. A promo audio sample has previously been released in late 2014.