| Rank | Student | Grade | School | Year | | ER | IP | ERA |
| 1 | Kacey Marshall | Sr | New Franklin | 1989 | | 0 | 108 | .000 |
| 2 | Jill Wilcoxson | Sr | North Harrison | 1996 | | 1 | 121.2 | .058 |
| 3 | Lauren Delaney | So | Helias Catholic | 2003 | | 2 | 168 | .083 |
| 4 | Jacquelyn Bishop | Sr | Kirksville | 2009 | | 2 | 164.1 | .085 |
| 5 | Lauren Delaney | Sr | Helias Catholic | 2005 | | 2 | 160 | .088 |
| 6 | Lauren Delaney | Jr | Helias Catholic | 2004 | | 2 | 137 | .102 |
| 7 | Jen Bruck | Sr | Ft. Zumwalt West | 2003 | | 2 | 136 | .103 |
| 8 | Jennifer Kempf | Sr | Bishop LeBlond | 2004 | | 3 | 191.2 | .110 |
| 9 | Chelsea Fuemmeler | Jr | Salisbury | 2004 | | 3 | 190 | .111 |
| 10 | Mac Morgan | Jr | Sherwood | 2019 | | 3 | 175.1 | .120 |
| 11 | Kenya Fuemmeler | Sr | Salisbury | 2002 | | 3 | 171 | .123 |
| 12 | Olivia Nicole Hemme | Jr | Concordia | 2023 | | 9 | 117.1 | .537 |
| 13 | Jaylynn J Brown | So | Centralia | 2024 | | 12 | 154 | .545 |
| 14 | Hannah Carter | Jr | South Harrison | 2022 | | 13 | 149 | .611 |
| 15 | Brittany Nimmo | Sr | Ozark | 2014 | | 24 | 162.2 | 1.033 |
| 16 | Maddy Colin | Jr | College Heights Christian | 2022 | | 21 | 141.1 | 1.040 |
| 17 | Maddy Colin | So | College Heights Christian | 2021 | | 20 | 131 | 1.069 |
| 18 | Anna Grace Christ | Sr | Rock Bridge | 2022 | | 17 | 109 | 1.092 |
| 19 | Taylor Brown | Jr | Washington | 2022 | | 20 | 125 | 1.120 |
| 20 | Jordyn Foley | Sr | Ozark | 2022 | | 40 | 171.2 | 1.631 |
| 21 | Hailey Presley | Sr | Marion C. Early | 2023 | | 58 | 205.1 | 1.977 |
| 22 | Zoe Martin | Sr | Sacred Heart | 2023 | | 49 | 121 | 2.835 |