O.J. Simpson has the most rushing yards by a Bills running back in a game, with 273 yards versus the Lions on November 25, 1976.

Interpreted as:

most rushing yards by a bills running back in a regular-season game

	NAME	RUSH YDS	DATE	TM		OPP	ATT	YPC	RUSH TD	REC YDS	REC	TRG	AVG	REC TD
1	O.J. Simpson	273	11/25/1976	BUF	@	DET	29	9.4	2	0	0			0
2	O.J. Simpson	250	9/16/1973	BUF	@	NE	29	8.6	2	0	0			0
3	Cookie Gilchrist C. Gilchrist	243	12/8/1963	BUF	vs	NYJ	36	6.8	5	0	0			0
4	O.J. Simpson	227	9/28/1975	BUF	@	PIT	28	8.1	1	0	0			0
5	O.J. Simpson	219	12/9/1973	BUF	vs	NE	22	10.0	1	0	0			0
6	James Cook III J. Cook III	216	10/26/2025	BUF	@	CAR	19	11.4	2	0	0	0		0
7	Thurman Thomas T. Thomas	214	9/24/1990	BUF	@	NYJ	18	11.9	0	5	3		1.7	0
8	Fred Jackson F. Jackson	212	1/3/2010	BUF	vs	IND	33	6.4	0	15	2	2	7.5	1
9	Terry Miller T. Miller	208	11/26/1978	BUF	vs	NYG	21	9.9	2	7	2		3.5	0
10	Greg Bell G. Bell	206	11/18/1984	BUF	vs	DAL	27	7.6	1	12	2		6.0	1
11	O.J. Simpson	203	12/5/1976	BUF	@	MIA	24	8.5	1	12	2		6.0	0
12	O.J. Simpson	200	12/16/1973	BUF	@	NYJ	34	5.9	1	0	0			0
13	O.J. Simpson	197	11/17/1975	BUF	@	CIN	17	11.6	2	21	2		10.5	0
14	O.J. Simpson	189	10/29/1972	BUF	vs	PIT	22	8.6	1	7	3		2.3	0
15	Joe Cribbs J. Cribbs	185	12/4/1983	BUF	@	KC	36	5.1	0	0	0			0
16	O.J. Simpson	185	12/14/1975	BUF	@	NE	21	8.8	1	28	2		14.0	0
17	Kenneth Davis K. Davis	181	11/22/1992	BUF	vs	ATL	20	9.1	2	4	1		4.0	0
18	James Cook III J. Cook III	179	12/17/2023	BUF	vs	DAL	25	7.2	1	42	2	3	21.0	1
19	O.J. Simpson	173	9/21/1975	BUF	vs	NYJ	32	5.4	2	5	1		5.0	0
20	O.J. Simpson	171	12/12/1976	BUF	@	BAL	28	6.1	1	18	1		18.0	0
21	O.J. Simpson	171	10/7/1973	BUF	vs	PHI	27	6.3	1	33	3		11.0	0
22	C.J. Spiller	169	9/9/2012	BUF	@	NYJ	14	12.1	1	25	2	3	12.5	0
23	Travis Henry T. Henry	169	12/7/2003	BUF	vs	NYJ	32	5.3	1	6	1	1	6.0	0
24	Travis Henry T. Henry	167	10/19/2003	BUF	vs	WAS	31	5.4	2	13	1	2	13.0	0
25	Joe Cribbs J. Cribbs	166	9/25/1983	BUF	vs	HOU	22	7.5	1	0	0			0

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Results may be incomplete. StatMuse has complete game-level data for rushing yards going back to the 1960 season.

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Sun 12/21	BUF	@	CLE	1:00 PM
Sun 12/28	PHI	@	BUF	4:25 PM
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Patriots	11	3	0	.786
Bills	10	4	0	.714
Dolphins - e	6	8	0	.429
Jets - e	3	11	0	.214
AFC North	W	L	T	PCT
Steelers	8	6	0	.571
Ravens	7	7	0	.500
Bengals - e	4	10	0	.286
Browns - e	3	11	0	.214
AFC South	W	L	T	PCT
Jaguars	10	4	0	.714
Texans	9	5	0	.643
Colts	8	6	0	.571
Titans - e	2	12	0	.143
AFC West	W	L	T	PCT
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Chiefs - e	6	8	0	.429
Raiders - e	2	12	0	.143

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Eagles	9	5	0	.643
Cowboys	6	7	1	.464
Commanders - e	4	10	0	.286
Giants - e	2	12	0	.143
NFC North	W	L	T	PCT
Bears	10	4	0	.714
Packers	9	4	1	.679
Lions	8	6	0	.571
Vikings - e	6	8	0	.429
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Buccaneers	7	7	0	.500
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Falcons - e	5	9	0	.357
Saints - e	4	10	0	.286
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Rams - x	11	3	0	.786
Seahawks	11	3	0	.786
49ers	10	4	0	.714
Cardinals - e	3	11	0	.214