| 1 | Wed Oct 22 | at Knicks | L111-119 | 0-1 | .000 | ESPN | Madison Square Garden · Manhattan, NY |
| 2 | Fri Oct 24 | at Nets | W131-124 | 1-1 | .500 | | Barclays Center · Brooklyn, NY |
| 3 | Sun Oct 26 | vs Bucks | W118-113 | 2-1 | .667 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 4 | Mon Oct 27 | at Pistons | W116-95 | 3-1 | .750 | Peacock | Little Caesars Arena · Detroit, MI |
| 5 | Wed Oct 29 | at Celtics | L105-125 | 3-2 | .600 | ESPN | TD Garden · Boston, MA |
| 6 | Fri Oct 31 | vs Raptors | L101-112 | 3-3 | .500 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 7 | Sun Nov 2 | vs Hawks | W117-109 | 4-3 | .571 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 8 | Wed Nov 5 | vs 76ers | W132-121 | 5-3 | .625 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 9 | Fri Nov 7 | at Wizards | W148-115 | 6-3 | .667 | | Capital One Arena · Washington, D.C. |
| 10 | Sat Nov 8 | vs Bulls | W128-122 | 7-3 | .700 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 11 | Mon Nov 10 | at Heat | L138-140 (OT) | 7-4 | .636 | | Kaseya Center · Miami, FL |
| 12 | Wed Nov 12 | at Heat | W130-116 | 8-4 | .667 | | Kaseya Center · Miami, FL |
| 13 | Thu Nov 13 | vs Raptors | L113-126 | 8-5 | .615 | NBA TV | Rocket Mortgage FieldHouse · Cleveland, OH |
| 14 | Sat Nov 15 | vs Grizzlies | W108-100 | 9-5 | .643 | NBA TV | Rocket Mortgage FieldHouse · Cleveland, OH |
| 15 | Mon Nov 17 | vs Bucks | W118-106 | 10-5 | .667 | Peacock | Rocket Mortgage FieldHouse · Cleveland, OH |
| 16 | Wed Nov 19 | vs Rockets | L104-114 | 10-6 | .625 | ESPN | Rocket Mortgage FieldHouse · Cleveland, OH |
| 17 | Fri Nov 21 | vs Pacers | W120-109 | 11-6 | .647 | Amazon | Rocket Mortgage FieldHouse · Cleveland, OH |
| 18 | Sun Nov 23 | vs Clippers | W120-105 | 12-6 | .667 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 19 | Mon Nov 24 | at Raptors | L99-110 | 12-7 | .632 | Peacock | Scotiabank Arena · Toronto, ON |
| 20 | Fri Nov 28 | at Hawks | L123-130 | 12-8 | .600 | | State Farm Arena · Atlanta, GA |
| 21 | Sun Nov 30 | vs Celtics | L115-117 | 12-9 | .571 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 22 | Mon Dec 1 | at Pacers | W135-119 | 13-9 | .591 | | Gainbridge Fieldhouse · Indianapolis, IN |
| 23 | Wed Dec 3 | vs Blazers | L110-122 | 13-10 | .565 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 24 | Fri Dec 5 | vs Spurs | W130-117 | 14-10 | .583 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 25 | Sat Dec 6 | vs Warriors | L94-99 | 14-11 | .560 | NBA TV | Rocket Mortgage FieldHouse · Cleveland, OH |
| 26 | Fri Dec 12 | at Wizards | W130-126 | 15-11 | .577 | | Capital One Arena · Washington, D.C. |
| 27 | Sun Dec 14 | vs Hornets | L111-119 (OT) | 15-12 | .556 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 28 | Wed Dec 17 | at Bulls | L111-127 | 15-13 | .536 | | United Center · Chicago, IL |
| 29 | Fri Dec 19 | vs Bulls | L125-136 | 15-14 | .517 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 30 | Mon Dec 22 | vs Hornets | W139-132 | 16-14 | .533 | Peacock | Rocket Mortgage FieldHouse · Cleveland, OH |
| 31 | Tue Dec 23 | vs Pelicans | W141-118 | 17-14 | .548 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 32 | Thu Dec 25 | at Knicks | L124-126 | 17-15 | .531 | Disney XD | Madison Square Garden · Manhattan, NY |
| 33 | Sat Dec 27 | at Rockets | L100-117 | 17-16 | .515 | | Toyota Center · Houston, TX |
| 34 | Mon Dec 29 | at Spurs | W113-101 | 18-16 | .529 | Peacock | AT&T Center · San Antonio, TX |
| 35 | Wed Dec 31 | vs Suns | W129-113 | 19-16 | .543 | NBA TV | Rocket Mortgage FieldHouse · Cleveland, OH |
| 36 | Fri Jan 2 | vs Nuggets | W113-108 | 20-16 | .556 | Amazon | Rocket Mortgage FieldHouse · Cleveland, OH |
| 37 | Sun Jan 4 | vs Pistons | L110-114 | 20-17 | .541 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 38 | Tue Jan 6 | at Pacers | W120-116 | 21-17 | .553 | | Gainbridge Fieldhouse · Indianapolis, IN |
| 39 | Thu Jan 8 | at T-wolves | L122-131 | 21-18 | .538 | | Target Center · Minneapolis, MN |
| 40 | Sat Jan 10 | vs T-wolves | W146-134 | 22-18 | .550 | Amazon | Rocket Mortgage FieldHouse · Cleveland, OH |
| 41 | Mon Jan 12 | vs Jazz | L112-123 | 22-19 | .537 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 42 | Wed Jan 14 | at 76ers | W133-107 | 23-19 | .548 | ESPN | Wells Fargo Center · Philadelphia, PA |
| 43 | Fri Jan 16 | at 76ers | W117-115 | 24-19 | .558 | ESPN | Wells Fargo Center · Philadelphia, PA |
| 44 | Mon Jan 19 | vs Thunder | L104-136 | 24-20 | .545 | Peacock | Rocket Mortgage FieldHouse · Cleveland, OH |
| 45 | Wed Jan 21 | at Hornets | W94-87 | 25-20 | .556 | ESPN | Spectrum Center · Charlotte, NC |
| 46 | Fri Jan 23 | vs Kings | W123-118 | 26-20 | .565 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 47 | Sat Jan 24 | at Magic | W119-105 | 27-20 | .574 | | Kia Center · Orlando, FL |
| 48 | Mon Jan 26 | vs Magic | W114-98 | 28-20 | .583 | Peacock | Rocket Mortgage FieldHouse · Cleveland, OH |
| 49 | Wed Jan 28 | vs Lakers | W129-99 | 29-20 | .592 | ESPN | Rocket Mortgage FieldHouse · Cleveland, OH |
| 50 | Fri Jan 30 | at Suns | L113-126 | 29-21 | .580 | | Mortgage Matchup Center · Phoenix, AZ |
| 51 | Sun Feb 1 | at Blazers | W130-111 | 30-21 | .588 | | Moda Center · Portland, OR |
| 52 | Wed Feb 4 | at Clippers | W124-91 | 31-21 | .596 | | Intuit Dome · Inglewood, CA |
| 53 | Sat Feb 7 | at Kings | W132-126 | 32-21 | .604 | | Golden 1 Center · Sacramento, CA |
| 54 | Mon Feb 9 | at Nuggets | W119-117 | 33-21 | .611 | | Ball Arena · Denver, CO |
| 55 | Wed Feb 11 | vs Wizards | W138-113 | 34-21 | .618 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| --all-star break-- |
| 56 | Thu Feb 19 | vs Nets | W112-84 | 35-21 | .625 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 57 | Fri Feb 20 | at Hornets | W118-113 | 36-21 | .632 | | Spectrum Center · Charlotte, NC |
| 58 | Sun Feb 22 | at Thunder | L113-121 | 36-22 | .621 | ABC | Paycom Center · Oklahoma City, OK |
| 59 | Tue Feb 24 | vs Knicks | W109-94 | 37-22 | .627 | Peacock | Rocket Mortgage FieldHouse · Cleveland, OH |
| 60 | Wed Feb 25 | at Bucks | L116-118 | 37-23 | .617 | | Fiserv Forum · Milwaukee, WI |
| 61 | Fri Feb 27 | at Pistons | L119-122 (OT) | 37-24 | .607 | ESPN | Little Caesars Arena · Detroit, MI |
| 62 | Sun Mar 1 | at Nets | W106-102 | 38-24 | .613 | | Barclays Center · Brooklyn, NY |