After a few live shows in Europe, Opeth returned to work on their next album, with Porcupine Tree's Steven Wilson producing. "This time it was tough", Åkerfeldt said, "I feel pleasantly blown away by the immense result, though. It was indeed worth the effort." Wilson also pushed the band to use new sounds and production techniques. "Steve guided us into the realms of 'strange' noises for guitars and voice", Åkerfeldt said. Opeth released its fifth studio album, "Blackwater Park", on February 21, 2001. This release encouraged Opeth to go on their first world tour, headlined Europe and playing to a crowd of 60,000 at the 2001 Wacken Open Air festival in Germany.
After touring in support of "Blackwater Park", Opeth returned home and began writing for the next album, but Åkerfeldt had trouble coming up with new material: "I wanted to write something heavier than we'd ever done, still I had all these great mellow parts and arrangements which I didn't want to go to waste." Jonas Renkse of Katatonia, a long-time friend of Åkerfeldt, suggested writing music for two separate albums — one heavy and one soft. Excited about the idea, Åkerfeldt agreed without asking his band mates or record label. While his band mates liked the idea of recording two separate albums, Åkerfeldt had to convince the label: "I had to lie somewhat... saying that we could do this recording very soon, it won't cost more than a regular single album". With most of the material written, the band rehearsed just once before entering the studio, again with producer Steven Wilson in Studio Fredman. Under pressure to complete both albums at the same time, Åkerfeldt said the recording process was "the toughest test of our history." After recording basic tracks, the band moved production to England to mix the heavy album, "Deliverance", with Andy Sneap at Backstage Studios. ""Deliverance" was so badly recorded, without any organisation whatsoever," Åkerfeldt claimed, that Sneap "is credited as a 'saviour' in the sleeve, as he surely saved much of the recording."
"Deliverance" was released on November 4, 2002, and debuted at number 19 on the US Top Independent Albums chart, marking the band's first US chart appearance. Allmusic stated, ""Deliverance" is altogether more subtle than any of its predecessors, approaching listeners with haunting nuances and masterful dynamics rather than overwhelming them with sheer mass and complexity." Opeth played a single concert in Stockholm, then returned to the UK to finish recording vocals for the second of the two albums, "Damnation", at Steve Wilson's No Man's Land Studios. Although Åkerfeldt first believed the band could not finish both albums, Opeth completed "Deliverance" and "Damnation" in just seven weeks of studio time, which was the same amount spent on "Blackwater Park" alone. "Damnation" was released on April 14, 2003, and gained the band its first appearance on the US "Billboard" 200 at number 192. The album also won the band a 2003 Swedish Grammy Award for "Best Hard Rock Performance". The band launched its biggest tour yet, playing nearly 200 shows in 2003 and 2004. Opeth performed three special shows in Europe with two song lists each — one acoustic set and one heavy set. The band recorded its first DVD, "Lamentations: Live at Shepherd's Bush Empire 2003", at Shepherd's Bush Empire in London. The DVD featured a two-hour performance, including the entire "Damnation" album, as well as several songs from "Deliverance" and "Blackwater Park", and a one-hour documentary about the recording of "Deliverance" and "Damnation". The DVD was certified Gold in Canada.
Opeth was scheduled to perform in Jordan in late 2003 without a crew due to the fear of terrorist attacks in the Middle East. Opeth's tour manager distributed 6,000 tickets for the concert, but before the band left for Jordan, Lopez called Åkerfeldt saying he was having an anxiety attack and could not perform, forcing the band to cancel the show. In early 2004, Lopez was sent home from Canada after more anxiety attacks on tour. Opeth decided not to cancel the rest of the tour, and Lopez's drum tech filled in for two concerts. Opeth asked drummer Gene Hoglan of Strapping Young Lad to fill in. Lopez eventually returned to Opeth for the Seattle show on the final leg of the "Deliverance" and "Damnation" tour. Per Wiberg also joined the band on keyboards, and after more than a year on tour, Opeth went back home to start writing more new songs in 2004.
Opeth's European label, Music for Nations, closed its doors in 2005 and the band signed with Roadrunner Records. After writing material for their eighth album in late 2004, the band rehearsed for three weeks before entering the studio, the first time they rehearsed since the 1998 album, "My Arms, Your Hearse". Opeth recorded at Fascination Street Studios in Örebro, Sweden, from March 18 to June 1, 2005, and released the album "Ghost Reveries" on August 30, 2005, again to critical and commercial success. The album debuted at number 64 in the US, and number nine in Sweden, higher than any other Opeth release. Keith Bergman of Blabbermouth.net gave the album 10 out of 10, one of only 17 albums to achieve a perfect rating from the site.
On May 12, 2006, Martin Lopez announced that he had officially parted ways with Opeth due to health problems, and he was replaced by Martin Axenrot. Opeth toured on the main stage of Gigantour in 2006, alongside Megadeth. "Ghost Reveries" was re-released on October 31, 2006, with a bonus cover version of Deep Purple's "Soldier of Fortune" and a DVD of the making of the album. A recording of Opeth's live performance at the Camden Roundhouse, in London, on November 9, 2006, was later released as the double live album "The Roundhouse Tapes". On May 17, 2007, Peter Lindgren stated he was leaving Opeth after 16 years. "The decision has been the toughest I've ever made but it is the right one to make at this point in my life," Lindgren said. "I feel that I simply have lost some of the enthusiasm and inspiration needed to participate in a band that has grown from a few guys playing the music we love to a worldwide industry." Ex-Arch Enemy guitarist Fredrik Åkesson replaced Lindgren, as Åkerfeldt explained, "Fredrik was the only name that popped up thinking about a replacement for Peter. In my opinion he's one of the top three guitar players out of Sweden. We all get along great as we've known each other for maybe four years and he already has the experience to take on the circus-like lifestyle we lead as members of Opeth."
In November 2007, after nearly 200 performances in support of "Ghost Reveries", Opeth entered Fascination Street Studios with Åkerfeldt producing. By January 2008, Opeth had recorded 13 songs, including three cover songs. The finished album, "Watershed", was released on June 3, 2008, and has seven tracks with cover songs included as bonus tracks on some versions. The album has since debuted at number 23 on the US "Billboard" 200, making it their highest-charting album yet. It enjoyed success in many other countries as well, entering the Australian ARIA album charts at number seven, while debuting at number one on Finland's official album chart. Opeth planned extensive touring in support of "Watershed", but some shows in Europe had to be cancelled because of some music festival cancellations and Åkerfeldt coming down with chicken pox. On January 25, 2009, Opeth played their first show in India at IIT Madras's cultural festival Saarang. On March 06, 2009 the band played in the Middle East at the annual Dubai Desert Rock Festival in Dubai. On March 26, 2009 it was announced that Opeth would take part in the first European Progressive Nation tour with bands Dream Theater, Bigelf and Unexpect. On April 24, 2009, Opeth headlined the first day of Metal Hammer Magazine's first UK metal music festival HammerFest.