| 20 | Fri Nov 28 | at Hawks | 7:30 PM | 11-8 | .579 | | State Farm Arena · Atlanta, GA |
| 21 | Sun Nov 30 | vs Celtics | 6:00 PM | 10-8 | .556 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 22 | Mon Dec 1 | at Pacers | 7:00 PM | 2-16 | .111 | | Gainbridge Fieldhouse · Indianapolis, IN |
| 23 | Wed Dec 3 | vs Blazers | 7:00 PM | 8-10 | .444 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 24 | Fri Dec 5 | vs Spurs | 7:30 PM | 11-5 | .688 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 25 | Sat Dec 6 | vs Warriors | 7:30 PM | 10-9 | .526 | NBA TV | Rocket Mortgage FieldHouse · Cleveland, OH |
| 26 | Wed Dec 17 | at Bulls | 8:00 PM | 9-8 | .529 | | United Center · Chicago, IL |
| 27 | Fri Dec 19 | vs Bulls | 7:30 PM | 9-8 | .529 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 28 | Mon Dec 22 | vs Hornets | 7:00 PM | 4-14 | .222 | Peacock | Rocket Mortgage FieldHouse · Cleveland, OH |
| 29 | Tue Dec 23 | vs Pelicans | 7:30 PM | 3-16 | .158 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 30 | Thu Dec 25 | at Knicks | 12:00 PM | 11-6 | .647 | ABC | Madison Square Garden · Manhattan, NY |
| 31 | Sat Dec 27 | at Rockets | 8:00 PM | 11-4 | .733 | | Toyota Center · Houston, TX |
| 32 | Mon Dec 29 | at Spurs | 8:00 PM | 11-5 | .688 | NBC | AT&T Center · San Antonio, TX |
| 33 | Wed Dec 31 | vs Suns | 3:30 PM | 11-7 | .611 | NBA TV | Rocket Mortgage FieldHouse · Cleveland, OH |
| 34 | Fri Jan 2 | vs Nuggets | 7:30 PM | 13-4 | .765 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 35 | Sun Jan 4 | vs Pistons | 2:00 PM | 15-3 | .833 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 36 | Tue Jan 6 | at Pacers | 7:00 PM | 2-16 | .111 | | Gainbridge Fieldhouse · Indianapolis, IN |
| 37 | Thu Jan 8 | at T-wolves | 8:00 PM | 10-8 | .556 | | Target Center · Minneapolis, MN |
| 38 | Sat Jan 10 | vs T-wolves | 1:00 PM | 10-8 | .556 | Amazon | Rocket Mortgage FieldHouse · Cleveland, OH |
| 39 | Mon Jan 12 | vs Jazz | 7:00 PM | 5-12 | .294 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 40 | Wed Jan 14 | at 76ers | 7:00 PM | 9-8 | .529 | ESPN | Wells Fargo Center · Philadelphia, PA |
| 41 | Fri Jan 16 | at 76ers | 7:00 PM | 9-8 | .529 | | Wells Fargo Center · Philadelphia, PA |
| 42 | Mon Jan 19 | vs Thunder | 2:30 PM | 18-1 | .947 | NBC | Rocket Mortgage FieldHouse · Cleveland, OH |
| 43 | Wed Jan 21 | at Hornets | 7:00 PM | 4-14 | .222 | ESPN | Spectrum Center · Charlotte, NC |
| 44 | Fri Jan 23 | vs Kings | 7:30 PM | 5-13 | .278 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 45 | Sat Jan 24 | at Magic | 7:00 PM | 11-8 | .579 | | Amway Center · Orlando, FL |
| 46 | Mon Jan 26 | vs Magic | 7:00 PM | 11-8 | .579 | Peacock | Rocket Mortgage FieldHouse · Cleveland, OH |
| 47 | Wed Jan 28 | vs Lakers | 7:00 PM | 13-4 | .765 | ESPN | Rocket Mortgage FieldHouse · Cleveland, OH |
| 48 | Fri Jan 30 | at Suns | 9:00 PM | 11-7 | .611 | | Footprint Center · Phoenix, AZ |
| 49 | Sun Feb 1 | at Blazers | 9:00 PM | 8-10 | .444 | | Moda Center · Portland, OR |
| 50 | Wed Feb 4 | at Clippers | 10:30 PM | 5-13 | .278 | | Intuit Dome · Inglewood, CA |
| 51 | Sat Feb 7 | at Kings | 10:00 PM | 5-13 | .278 | | Golden 1 Center · Sacramento, CA |
| 52 | Mon Feb 9 | at Nuggets | 9:00 PM | 13-4 | .765 | | Ball Arena · Denver, CO |
| 53 | Wed Feb 11 | vs Wizards | 7:00 PM | 2-15 | .118 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| --all-star break-- |
| 54 | Thu Feb 19 | vs Nets | 7:00 PM | 3-14 | .176 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 55 | Fri Feb 20 | at Hornets | 7:00 PM | 4-14 | .222 | | Spectrum Center · Charlotte, NC |
| 56 | Sun Feb 22 | at Thunder | 1:00 PM | 18-1 | .947 | ABC | Paycom Center · Oklahoma City, OK |
| 57 | Tue Feb 24 | vs Knicks | 8:00 PM | 11-6 | .647 | NBC | Rocket Mortgage FieldHouse · Cleveland, OH |
| 58 | Wed Feb 25 | at Bucks | 8:00 PM | 8-11 | .421 | | Fiserv Forum · Milwaukee, WI |
| 59 | Fri Feb 27 | at Pistons | 7:00 PM | 15-3 | .833 | ESPN | Little Caesars Arena · Detroit, MI |
| 60 | Sun Mar 1 | at Nets | 3:30 PM | 3-14 | .176 | | Barclays Center · Brooklyn, NY |
| 61 | Tue Mar 3 | vs Pistons | 7:00 PM | 15-3 | .833 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 62 | Sun Mar 8 | vs Celtics | 1:00 PM | 10-8 | .556 | ABC | Rocket Mortgage FieldHouse · Cleveland, OH |
| 63 | Mon Mar 9 | vs 76ers | 7:00 PM | 9-8 | .529 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 64 | Wed Mar 11 | at Magic | 7:30 PM | 11-8 | .579 | ESPN | Amway Center · Orlando, FL |
| 65 | Fri Mar 13 | at Mavericks | 8:30 PM | 5-14 | .263 | | American Airlines Center · Dallas, TX |
| 66 | Sun Mar 15 | vs Mavericks | 3:30 PM | 5-14 | .263 | NBA TV | Rocket Mortgage FieldHouse · Cleveland, OH |
| 67 | Tue Mar 17 | at Bucks | 8:00 PM | 8-11 | .421 | NBC | Fiserv Forum · Milwaukee, WI |
| 68 | Thu Mar 19 | at Bulls | 8:00 PM | 9-8 | .529 | | United Center · Chicago, IL |
| 69 | Sat Mar 21 | at Pelicans | 7:00 PM | 3-16 | .158 | | Smoothie King Center · New Orleans, LA |
| 70 | Tue Mar 24 | vs Magic | 8:00 PM | 11-8 | .579 | NBC | Rocket Mortgage FieldHouse · Cleveland, OH |
| 71 | Wed Mar 25 | vs Heat | 7:30 PM | 13-6 | .684 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 72 | Fri Mar 27 | vs Heat | 7:30 PM | 13-6 | .684 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 73 | Mon Mar 30 | at Jazz | 9:00 PM | 5-12 | .294 | | Vivint Arena · Salt Lake City, UT |
| 74 | Tue Mar 31 | at Lakers | 10:30 PM | 13-4 | .765 | | Crypto.com Arena · Los Angeles, CA |
| 75 | Thu Apr 2 | at Warriors | 10:00 PM | 10-9 | .526 | Amazon | Chase Center · San Francisco, CA |
| 76 | Sun Apr 5 | vs Pacers | 6:00 PM | 2-16 | .111 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 77 | Mon Apr 6 | at Grizzlies | 8:00 PM | 7-12 | .368 | | FedExForum · Memphis, TN |
| 78 | Wed Apr 8 | vs Hawks | 7:00 PM | 11-8 | .579 | | Rocket Mortgage FieldHouse · Cleveland, OH |
| 79 | Fri Apr 10 | at Hawks | 7:30 PM | 11-8 | .579 | Amazon | State Farm Arena · Atlanta, GA |
| 80 | Sun Apr 12 | vs Wizards | 6:00 PM | 2-15 | .118 | | Rocket Mortgage FieldHouse · Cleveland, OH |