| 03 Apr 22 | r00  | FC MotownFC Motown | 1 - 0 | West Chester United SCWest Chester |
| 06 Apr 22 | r00 | Pittsburgh RiverhoundsPittsburgh Ri | 2 - 0 | Maryland Bobcats FCMaryland Bobc |
| 06 Apr 22 | r00 | Charlotte IndependenceCharlotte Ind | 2 - 4 | North Carolina Fusion U23North Carolin |
| 06 Apr 22 | r00 | Detroit City FCDetroit City | 3 - 0 | Michigan Stars FCMichigan Star |
| 06 Apr 22 | r00 | Tampa Bay RowdiesTampa Bay Row | 6 - 0 | The Villages SCThe Villages |
| 06 Apr 22 | r00 | Indy ElevenIndy Eleven | 0 - 2 | St. Louis City SC 2St. Louis Cit |
| 06 Apr 22 | r00 | Union OmahaUnion Omaha | 2 - 1 | Des Moines MenaceDes Moines Me |
| 06 Apr 22 | r00 | San AntonioSan Antonio | 3 - 1 | DFeeters KicksDFeeters Kick |
| 06 Apr 22 | r00 | Tulsa RoughnecksTulsa Roughne | 2 - 1 | Tulsa AthleticsTulsa Athleti |
| 06 Apr 22 | r00 | New Mexico UnitedNew Mexico Un | 5 - 0 | Las Vegas Legends FCLas Vegas Leg |
| 06 Apr 22 | r00 | Central Valley Fuego FCCentral Valle | 4 - 1 | El Paso LocomotiveEl Paso Locom |
| 06 Apr 22 | r00 | Orange County SCOrange County | 5 - 2 | LA ForceLA Force |
| 07 Apr 22 | r00  | North Carolina FCNorth Carolin | 1 - 2 | Rio Grande ValleyRio Grande Va |
| 07 Apr 22 | r00 | West Chester United SCWest Chester | 1 - 0 | AC Syracuse PulseAC Syracuse P |
| 07 Apr 22 | r00 | Miami FCMiami FC | 3 - 0 | Miami UnitedMiami United |
| 07 Apr 22 | r00 | Louisville CityLouisville Ci | 1 - 0 | Chattanooga Red Wolves SCChattanooga R |
| 07 Apr 22 | r00 | Flower City UnionFlower City U | 0 - 1 | Western Mass PioneersWestern Mass |
| 07 Apr 22 | r00 | Forward Madison FCForward Madis | 3 - 0 | Cleveland SCCleveland SC |
| 07 Apr 22 | r00 | Northern Virginia FCNorthern Virg | 0 - 1 | Richmond KickersRichmond Kick |
| 07 Apr 22 | r00 | Colorado SpringsColorado Spri | 0 - 1 | Northern Colorado HailstoNorthern Colo |
| 07 Apr 22 | r00 | Bay Cities FCBay Cities FC | 2 - 1 | Monterey Bay FCMonterey Bay |
| 07 Apr 22 | r00 | ASC San DiegoASC San Diego | 1 - 2 | San Diego LoyalSan Diego Loy |
| 07 Apr 22 | r00 | FC TucsonFC Tucson | 3 - 2 | Las Vegas LightsLas Vegas Lig |
| 07 Apr 22 | r00 | Phoenix RisingPhoenix Risin | 1 - 0 | Valley United FCValley United |
| 07 Apr 22 | r00 | Charleston BatteryCharleston Ba | 0 - 1 | Tormenta FCTormenta FC |
| 07 Apr 22 | r00 | Rochester New York FCRochester New | 1 - 0 | Lansdowne BhoysLansdowne Bho |
| 07 Apr 22 | r00 | Hartford AthleticHartford Athl | 3 - 1 | Oyster Bay UnitedOyster Bay Un |
| 08 Apr 22 | r00 | Chattanooga FCChattanooga F | 3 - 1 | Memphis 901Memphis 901 |
| 08 Apr 22 | r00 | Greenville Triumph SCGreenville Tr | 2 - 0 | Oakland RootsOakland Roots |
| 08 Apr 22 | r00 | Birmingham LegionBirmingham Le | 3 - 1 | Southern StatesSouthern Stat |
| 08 Apr 22 | r00  | California United StrikerCalifornia Un | 5 - 0 | San Fernando ValleySan Fernando |
| 08 Apr 22 | r00 | Sacramento RepublicSacramento Re | 6 - 0 | Portland Timbers U23Portland Timb |
| 20 Apr 22 | r00 | FC CincinnatiFC Cincinnati | 2 - 0 | Pittsburgh RiverhoundsPittsburgh Ri |
| 20 Apr 22 | r00 | Miami FCMiami FC | 0 - 1 | Inter MiamiInter Miami |
| 20 Apr 22 | r00 | Flower City UnionFlower City U | 0 - 3 | DC UnitedDC United |
| 20 Apr 22 | r00 | Detroit City FCDetroit City | 2 - 1 | Columbus CrewColumbus Crew |
| 20 Apr 22 | r00 | Birmingham LegionBirmingham Le | 0 - 2 | Tormenta FCTormenta FC |
| 20 Apr 22 | r00 | Chicago FireChicago Fire | 2 - 2 | Union OmahaUnion Omaha |
| 20 Apr 22 | r00 | Houston DynamoHouston Dynam | 2 - 1 | Rio Grande ValleyRio Grande Va |
| 20 Apr 22 | r00 | FC DallasFC Dallas | 2 - 1 | Tulsa RoughnecksTulsa Roughne |
| 20 Apr 22 | r00 | FC TucsonFC Tucson | 1 - 2 | California United StrikerCalifornia Un |
| 20 Apr 22 | r00 | L.A. GalaxyL.A. Galaxy | 1 - 0 | San Diego LoyalSan Diego Loy |
| 20 Apr 22 | r00 | San Jose EarthquakesSan Jose Eart | 5 - 0 | Bay Cities FCBay Cities FC |
| 20 Apr 22 | r00 | Rochester New York FCRochester New | 2 - 2 | FC MotownFC Motown |
| 20 Apr 22 | r00 | Hartford AthleticHartford Athl | 1 - 2 | New York Red BullsNew York Red |
| 20 Apr 22 | r00 | Richmond KickersRichmond Kick | 1 - 0 | North Carolina Fusion U23North Carolin |
| 21 Apr 22 | r00 | Orlando CityOrlando City | 2 - 1 | Tampa Bay RowdiesTampa Bay Row |
| 21 Apr 22 | r00 | Forward Madison FCForward Madis | 0 - 2 | Minnesota UnitedMinnesota Uni |
| 21 Apr 22 | r00 | Greenville Triumph SCGreenville Tr | 1 - 2 | Charlotte FCCharlotte FC |
| 21 Apr 22 | r00 | Atlanta UnitedAtlanta Unite | 6 - 0 | Chattanooga FCChattanooga F |
| 21 Apr 22 | r00 | Louisville CityLouisville Ci | 0 - 0 | St. Louis City SC 2St. Louis Cit |
| 21 Apr 22 | r00 | San AntonioSan Antonio | 2 - 1 | Austin FCAustin FC |
| 21 Apr 22 | r00 | Real Salt LakeReal Salt Lak | 0 - 1 | Northern Colorado HailstoNorthern Colo |
| 21 Apr 22 | r00 | Sacramento RepublicSacramento Re | 2 - 1 | Central Valley Fuego FCCentral Valle |
| 21 Apr 22 | r00 | Los Angeles FCLos Angeles F | 5 - 1 | Orange County SCOrange County |
| 21 Apr 22 | r00 | Phoenix RisingPhoenix Risin | 2 - 1 | New Mexico UnitedNew Mexico Un |
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