Lowndes began karting at age nine and moved to circuit racing in 1991, driving a Van Diemen in the Motorcraft Formula Ford series. He won the Australian Formula Ford Championship in 1993, which earned him a place in that year's Formula Ford Festival in England where he finished third. In 1994 he contested Australia's Formula Brabham category, winning the Australian Silver Star against more modern machinery.
Still in 1994, Lowndes joined the Holden Racing Team as a test driver and made a dramatic impression at the Sandown 500 and Bathurst 1000, including a stunning overtake on the leading DJR Falcon of John Bowe in his first Sandown appearance — a pass he later admitted happened because he missed his braking marker.
Lowndes earned a full-time HRT seat for 1996 and immediately won the Australian Touring Car Championship by 79 points from reigning champion John Bowe, also claiming both the Sandown 500 and the Bathurst 1000 with teammate Greg Murphy. His Bathurst win made him the youngest-ever winner of the race and, with Murphy, the youngest-ever driver pairing to claim the Mount Panorama title.
Attracted by the prospect of Formula One, Lowndes signed a ten-year management deal with HRT owner Tom Walkinshaw and travelled to Europe in 1997 to contest the International Formula 3000 Championship with RSM Marko. He qualified sixth on debut at Silverstone but struggled throughout the season alongside highly rated teammate Juan Pablo Montoya and returned to Australia.
Back at HRT he won the 1998 championship and then a third consecutive title in 1999, finishing off the podium only once in the first 18 races. He suffered a spectacular rollover during the season at Calder Park after being tapped from behind, yet still clinched the championship at Bathurst.
Lowndes controversially switched from Holden to Ford for 2001, joining a new team headed by former driver Fred Gibson. Two difficult seasons followed as reliability problems and team instability undermined his results. After a brief stint at Ford Performance Racing in 2003 and 2004, Lowndes joined Triple Eight Race Engineering in 2005 and immediately flourished, finishing second in the championship with the most round victories and pole positions of any driver that season.
At the 2006 Bathurst 1000, Lowndes won over Rick Kelly by just half a second in one of the closest finishes in the race's history — his first Bathurst win since 1996 and an emotional victory, coming just weeks after the death of his long-time mentor Peter Brock. As inaugural winners, he and teammate Jamie Whincup were presented with the Peter Brock Trophy. Alongside Whincup, Lowndes won the Bathurst 1000 in 2007 and 2008 for three consecutive victories — only the third pairing in race history to achieve the feat.
Lowndes remained at Triple Eight through the era of Whincup's championship dominance, consistently finishing second in the standings across 2011, 2012, and 2013. In 2010, partnering five-time champion Mark Skaife, he won his fifth Bathurst 1000 and the Phillip Island 500. His 2015 season brought his sixth Bathurst victory alongside Steven Richards, equalling the Bathurst win tallies of Mark Skaife and Larry Perkins. He then surpassed them to stand alone with his seventh Bathurst 1000 win alongside Richards in 2018, achieving it in a record time of 6 hours 1 minute.
In 2015, Lowndes became the first driver to reach 100 championship race wins and holds the record for the most Bathurst 1000 podiums at 14.
On 5 July 2018, Lowndes announced his retirement from full-time competition at the end of that season, continuing as an endurance co-driver at Triple Eight. He won the Bathurst 1000 in 2020 and 2022 co-driving for Triple Eight alongside Shane van Gisbergen, later moving to Grove Racing for endurance duties from 2023.
Lowndes also won the Bathurst 12 Hour twice — in 2014 driving a Ferrari 458 GT3 for Maranello Motorsport alongside John Bowe, Peter Edwards, and Mika Salo, and again in 2017 alongside Whincup and Toni Vilander in a Ferrari 488 GT3. He ventured into off-road racing in 2010, winning the Australasian Safari on his first attempt.
On 11 June 2012, Lowndes received the Medal of the Order of Australia in the Queen's Birthday Honours. In March 2019, he was inducted into the Australian Motor Sport Hall of Fame.