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| Single-Season Strikeouts Leaderboard | |
| * - Indicates Hall of Fame |
| Rank | Player | Strikeouts | IP | Year | Career Leaderboard |
| 1. | Mark Prior * | 344 | 279.3 | 2009 | |
| 2. | Mark Prior * | 327 | 252.3 | 2013 | |
| 3. | Pedro Barranco | 326 | 267.0 | 2016 | |
| 4. | Brian Anderson | 325 | 273.7 | 2016 | |
| 5. | Jeremy Bonderman | 320 | 238.7 | 2012 | |
| 6. | Mark Prior * | 319 | 268.0 | 2007 | |
| 7. | Brett Evert | 318 | 242.3 | 2012 | |
| J.D. Martin | 318 | 242.7 | 2011 | ||
| 9. | Pedro Barranco | 317 | 254.3 | 2011 | |
| 10. | Ubaldo Jimenez | 309 | 228.3 | 2011 | |
| 11. | Pedro Barranco | 308 | 258.7 | 2009 | |
| 12. | Pedro Barranco | 305 | 240.0 | 2012 | |
| 13. | Brian Anderson | 304 | 282.7 | 2013 | |
| 14. | Jeremy Bonderman | 303 | 224.7 | 2011 | |
| Roy Halladay | 303 | 275.0 | 2009 | ||
| 16. | Pedro Barranco | 299 | 246.0 | 2013 | |
| Angel Moreno | 299 | 207.3 | 2011 | ||
| 18. | Mark Prior * | 297 | 244.3 | 2011 | |
| Mark Prior * | 297 | 260.3 | 2010 | ||
| 20. | Larry Strope | 296 | 261.0 | 2009 | |
| Kerry Wood | 296 | 224.0 | 2004 | ||
| 22. | Jeremy Bonderman | 295 | 231.7 | 2007 | |
| 23. | Pedro Galindo | 292 | 232.7 | 2015 | |
| Pedro Barranco | 292 | 239.3 | 2014 | ||
| Jeremy Bonderman | 292 | 244.7 | 2008 | ||
| Mark Prior * | 292 | 264.0 | 2006 | ||
| 27. | Lewis Washburn | 290 | 257.7 | 2019 | |
| J.D. Martin | 290 | 233.7 | 2012 | ||
| 29. | Brian Anderson | 289 | 285.3 | 2019 | |
| 30. | J.D. Martin | 287 | 224.3 | 2017 | |
| Darren Nigro | 287 | 239.7 | 2012 | ||
| Ubaldo Jimenez | 287 | 237.0 | 2010 | ||
| 33. | Condel Ortiz | 286 | 252.3 | 2014 | |
| J.D. Martin | 286 | 257.7 | 2009 | ||
| Jeremy Bonderman | 286 | 246.0 | 2009 | ||
| 36. | Roy Halladay | 285 | 264.7 | 2011 | |
| 37. | Korey Mathison | 284 | 290.7 | 2021 | |
| 38. | Matt Riley | 282 | 231.0 | 2011 | |
| 39. | Amadis Rodriguez | 281 | 252.3 | 2019 | |
| J.D. Martin | 281 | 226.7 | 2015 | ||
| Ubaldo Jimenez | 281 | 216.0 | 2013 | ||
| 42. | Larry Strope | 280 | 239.3 | 2015 | |
| 43. | Condel Ortiz | 279 | 243.0 | 2016 | |
| Condel Ortiz | 279 | 242.3 | 2015 | ||
| 45. | Larry Strope | 278 | 240.0 | 2010 | |
| 46. | Mark Prior * | 277 | 238.7 | 2008 | |
| 47. | Willie Leon | 276 | 250.7 | 2020 | |
| J.D. Martin | 276 | 231.0 | 2018 | ||
| Jeremy Bonderman | 276 | 207.3 | 2010 | ||
| Roy Halladay | 276 | 266.3 | 2006 | ||
| 51. | Augustine Stearn | 275 | 242.0 | 2022 | |
| Condel Ortiz | 275 | 237.3 | 2019 | ||
| Jason Schmidt | 275 | 270.3 | 2006 | ||
| 54. | Ubaldo Jimenez | 274 | 221.3 | 2014 | |
| Kerry Wood | 274 | 229.7 | 2009 | ||
| 56. | Pedro Barranco | 273 | 224.0 | 2017 | |
| 57. | Lewis Washburn | 272 | 230.0 | 2017 | |
| Brian Anderson | 272 | 269.7 | 2015 | ||
| Kerry Wood | 272 | 224.0 | 2008 | ||
| Randy Johnson | 272 | 254.0 | 2004 | ||
| 61. | Brian Anderson | 271 | 263.7 | 2020 | |
| J.D. Martin | 271 | 209.7 | 2016 | ||
| Rick Ankiel | 271 | 205.7 | 2013 | ||
| Roy Halladay | 271 | 268.7 | 2010 | ||
| Bobby Jenks | 271 | 238.7 | 2009 | ||
| 66. | Willie Leon | 270 | 268.7 | 2022 | |
| Dennis Baley | 270 | 253.7 | 2022 | ||
| Lewis Washburn | 270 | 243.0 | 2018 | ||
| Clint Nageotte | 270 | 227.0 | 2011 | ||
| Carlos Zambrano | 270 | 254.0 | 2009 | ||
| 71. | Augustine Stearn | 269 | 248.3 | 2021 | |
| Dennis Baley | 269 | 247.7 | 2020 | ||
| Roy Halladay | 269 | 241.0 | 2013 | ||
| 74. | Freddie Cooley | 268 | 257.3 | 2016 | |
| Dave Cedeno | 268 | 234.0 | 2012 | ||
| Bobby Jenks | 268 | 224.7 | 2012 | ||
| 77. | Brett Evert | 267 | 206.7 | 2011 | |
| 78. | Brian Anderson | 266 | 252.0 | 2021 | |
| J.D. Martin | 266 | 219.0 | 2014 | ||
| Mark Prior * | 266 | 206.3 | 2014 | ||
| Bobby Jenks | 266 | 206.0 | 2014 | ||
| Larry Strope | 266 | 222.7 | 2012 | ||
| 83. | Brian Anderson | 265 | 263.3 | 2014 | |
| Roger Heitman | 265 | 266.3 | 2012 | ||
| Roy Halladay | 265 | 240.7 | 2008 | ||
| 86. | Condel Ortiz | 264 | 257.3 | 2017 | |
| Roy Halladay | 264 | 243.0 | 2015 | ||
| Pedro Galindo | 264 | 212.3 | 2014 | ||
| Carlos Zambrano | 264 | 228.3 | 2013 | ||
| Richard Menzies | 264 | 227.3 | 2012 | ||
| J.D. Martin | 264 | 245.0 | 2010 | ||
| Barry Zito | 264 | 293.7 | 2009 | ||
| Rick Hummel | 264 | 248.7 | 2009 | ||
| 94. | Condel Ortiz | 263 | 244.0 | 2018 | |
| Pedro Barranco | 263 | 230.3 | 2015 | ||
| Josef Soliz | 263 | 216.7 | 2013 | ||
| 97. | Jason Schmidt | 262 | 261.3 | 2005 | |
| 98. | Amadis Rodriguez | 261 | 237.0 | 2020 | |
| 99. | Pedro Barranco | 260 | 244.3 | 2018 | |
| 100. | Augustine Stearn | 259 | 250.3 | 2017 |
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