Oosthuizen won The Open Championship in 2010 at St. Andrews to claim his first major title. He has four second-place finishes in majors, including the 2015 U.S. Open at Chambers Bay, when he shot a championship-record 199 for his final 54 holes to share second with Dustin Johnson. His final-round 67 included a 29 on the second nine, a feat only achieved three other times in U.S. Open history. He also finished as a runner-up in The Open Championship in 2015 at St. Andrews, falling in a three-hole aggregate playoff won by Zach Johnson, and lost to Bubba Watson in a playoff in the 2012 Masters. In 2017, he finished tied for second in the PGA Championship at Quail Hollow. Of his 14 worldwide victories, nine have come on the European Tour. Represented South Africa in the 2002 World Amateur Team Championship. Represented the International Team in the Presidents Cup in 2013, 2015, 2017 and 2019.
| Year | Site | Scores | To Par | Finish |
| 2020 | Winged Foot Golf Club (West Course) | 67-74-68-73--282 | +2 | 3rd |
| 2019 | Pebble Beach Golf Links | 66-70-70-72--278 | -6 | T-7 |
| 2018 | Shinnecock Hills Golf Club | 74-72-75-69--290 | +10 | T-16 |
| 2017 | Erin Hills | 74-70-68-73--285 | -3 | T-23 |
| 2016 | Oakmont Country Club | 75-65-74-73--287 | +7 | T-23 |
| 2015 | Chambers Bay | 77-66-66-67--276 | -4 | T-2 |
| 2014 | Pinehurst Resort & C.C. (Course No. 2) | 71-73-78-67--289 | +9 | T-40 |
| 2013 | Merion Golf Club | 75-WD | WD | |
| 2012 | The Olympic Club | 77-72 | +9 | MC |
| 2011 | Congressional Country Club | 69-73-71-67--280 | -4 | T-9 |
| 2010 | Pebble Beach Golf Links | 77-74 | +9 | MC |