Cazenovia Creek provides good fishing for smallmouth bass, and fly fishing for bass on warm summer evenings is popular on this stream. Minnow and crayfish imitations and streamer flies are very effective, especially in the faster sections. In the lower reaches, much of the stream is slate bottomed. There are numerous undercuts in the slate, and the bass will often use these as cover as they wait to ambush baitfish. Small spinners, poppers, and live bait are productive on this section.

Cazenovia Creek is also known for its good fishing for steelhead, which run up the creek from late fall through early spring. Steelhead are not stocked in this stream; these are all strays from the Buffalo River. Under the right water conditions (cold and sufficiently high), the fish enter Cazenovia Creek in surprisingly good numbers. The main stem of the stream provides a variety of water conditions, including a low waterfall, rapids, and calm, deeper water. The waterfall is the first significant obstacle the fish must clear when moving up Cazenovia Creek. These fish can run as far up as a dam located just downstream of Center Street in East Aurora (on the East Branch of Cazenovia Creek) and the dam at Bridge Street in West Valley (on the West Branch of Cazenovia Creek). The east and west branches of Cazenovia Creek join about 480 feet south of Quaker Road in East Aurora.

In addition to numerous road crossings, extensive public access to the main stem Cazenovia Creek is available in Cazenovia Park and Thomas Higgins Park in Buffalo, and in Mill Road Park and the Cazenovia Creek Fish and Wildlife Management Area in West Seneca (the map pin is located in the WMA).