Purpose: Topical application of nonivamide–nicoboxil cream to resting legs has been shown to enhance the level of oxygenated haemoglobin in leg muscles 15 min later. Here, we examined whether such application improves the performance of experienced cyclists in a subsequent 4-km time-trial. Methods: Nine male cyclists [26 ± 8 years; 176 ± 9 cm; 73.5 ± 12.8 kg; peak oxygen uptake: 50.7 ± 4.0 mL min−1 kg−1 (mean ± SD)] performed three 4-km time-trials on an ergometer with either topical application of nonivamide–nicoboxil cream (CREAM) or cream without active components (SHAM) to both their thigh muscles or no application (CONTROL). Results: Only the skin temperature immediately before and after the time-trial was higher with cream than SHAM and CONTROL (best p < 0.001, best d = 1.16). All other parameters evaluated, i.e., the average power output during the time-trial (p > 0.05, best d = 0.08), the tissue saturation index of the m. vastus lateralis (p > 0.05, best d = 0.57), cardiac output, heart rate, oxygen uptake, blood lactate concentration, and perceived exertion (p > 0.05, best d = 1.1) were similar under all three conditions. Conclusions: Our present findings reveal that topical application of cream containing nonivamide and nicoboxil to the thighs of cyclists prior to a 4-km time-trial does not improve their power output, saturation of the m. vastus lateralis with oxygen, oxygen uptake, heart rate, cardiac parameters, or perceived level of exertion.