Lionel Vital has the most career rushing yards per game, with 115.3 per game.

rushing yards per game leader all-time
VitalBrownSandersDavisDickersonElliottPaytonPortisCookSimsMartinWillhiteChubbSimpsonJamesPetersonCampbellFosterSmithLewisTomlinsonWilliamsTaylor115.3104.399.897.590.889.788.087.885.785.183.983.783.383.282.782.381.881.681.281.080.579.979.5
NAMEGPRUSH YDS/GRUSH YDSATTYPCRUSH TDREC YDSRECTRGAVGREC YDS/GREC TD
Lionel VitalLionel Vital3115.3346804.3213113.04.30
Jim BrownJim Brown118104.312,3122,3595.21062,4992629.521.220
Barry SandersBarry Sanders15399.815,2693,0625.0992,9213528.319.110
Terrell DavisTerrell Davis7897.57,6071,6554.6601,280169267.616.45
Eric DickersonEric Dickerson14690.813,2592,9964.4902,1372817.614.66
Ezekiel ElliottEzekiel Elliott7789.76,9051,5154.6512,0622573358.026.811
Walter PaytonWalter Payton19088.016,7263,8384.41104,5384929.223.915
Clinton PortisClinton Portis11387.89,9232,2304.4752,0182473388.217.95
Dalvin CookDalvin Cook4785.74,0278494.7351,3481602008.428.73
Billy SimsBilly Sims6085.15,1061,1314.5422,07218611.134.55
Curtis MartinCurtis Martin16883.914,1013,5184.0903,3294844096.919.810
Kevin WillhiteKevin Willhite383.7251534.703766.212.30
Nick ChubbNick Chubb4983.34,0807705.332612771017.912.52
O.J. SimpsonO.J. Simpson13583.211,2362,4044.7612,14220310.615.914
Edgerrin JamesEdgerrin James14882.712,2463,0284.0803,3644335847.822.711
Adrian PetersonAdrian Peterson18082.314,8203,1924.61182,4663014198.213.76
Earl CampbellEarl Campbell11581.89,4072,1874.3748061216.77.00
Arian FosterArian Foster8081.66,5271,4764.4542,3462553559.229.314
Emmitt SmithEmmitt Smith22681.218,3554,4094.21643,2245151306.314.311
Jamal LewisJamal Lewis13181.010,6072,5424.2581,8792212988.514.34
LaDainian TomlinsonLaDainian Tomlinson17080.513,6843,1744.31454,7726248687.628.117
Domanick WilliamsDomanick Williams4079.93,1957704.1231,2761542008.331.95
Jonathan TaylorJonathan Taylor2279.51,7483375.21651254609.523.32
Derrick HenryDerrick Henry8579.26,7291,3734.965846941259.010.03
George RogersGeorge Rogers9278.07,1761,6924.254368556.74.00
StatMuse has season-level data for rushing yards per game going back to the 1932 season.