NFL Network first reported the extent of the injury, and it was confirmed by ESPN's Adam Caplan.
Enemkpali's leg bent awkwardly as he was engaged with a blocker while rushing quarterback Scott Tolzien on a second-down incompletion.
The injury potentially further depletes the Bills' depth at outside linebacker. Rookie first-round pick Shaq Lawson underwent shoulder surgery in May; he's expected to be out until Week 6 at the earliest, a source told ESPN NFL Insider Adam Schefter. Veteran Manny Lawson remains out with a partially torn pectoral muscle.
Ryan said Lawson is expected to return by Week 1, but the coach indicated last week that veteran Lorenzo Alexander would receive the start if Lawson was not able to play.
"Well, we just got to hope we get Manny back soon," Ryan said. "I think that will obviously be a big help. I'm not saying we won't look for other possibilities. We have Lorenzo Alexander, who I feel really good about. You guys saw the kind of impact he has as a special teams player. I purposely held him out of some of the [defensive] snaps because when he was starting on all of those [special] teams, I don't want him starting on defense, also. But he's a very capable player."
Enemkpali started Saturday's game and had been running with the first-team defense in practice during training camp.
Now in his second season with the Bills, Enemkpali made headlines in August 2015, when he punched New York Jets quarterback Geno Smith, breaking his jaw. Enemkpali was released by the Jets and claimed off waivers by the Bills.