Cognitive performance is negatively affected by the presence of noise, which is seen as a distractor and a stressor, especially in hazardous occupational environments. The addition of musculoskeletal fatigue that commonly accompanies occupational work due to noise interruption can further elevate risk and compromise safety. The purpose of the study was to investigate the impact of both individual and a combination of noise interference and physical workload on simple and choice response time tasks. Sixteen healthy male and female participants (age: 20 ± 1 years; height: 169.48 ± 8.2 cm; weight: 67.93 ± 12.7 kg) performed a simple (SRT) and choice response task (CRT) with three Blazepod™ light response time systems by striking with the dominant lower extremity from a seated position while listening to noises from a construction site (65–85dB) through headphones. Participants then performed a low-intensity musculoskeletal fatigue task and completed the above measures again. Response times (RT) (ms) from three trials of SRT and CRT, both without and with noise interference, before (PRE) and after the workload (POST), were averaged, and a 2 (Noise) × 2 (workload) × 2 (task) repeated measure ANOVA and a 2 (Noise) × 2 (workload) repeated measure ANOVA were performed for SRT and CRT, respectively, using JASP at an alpha level of 0.05. Results revealed a significant interaction between workload task (p = 0.041), as well as a main effect significance for the workload (p = 0.007) and noise (p = 0.044). The main effect significance also existed for workload in SRT (p = 0.009) and for noise in CRT (p = 0.002). In SRT, RT was significantly faster during the POST fatigue measure, suggesting a possible cognitive arousal and a learning effect improvement rather than a negative fatigue effect. In both SRT and CRT, as well as individually in CRT, RT was significantly slower due to noise interruption, negatively impacting performance, especially in the more challenging CRT compared to SRT. Thus, findings from the current study suggest that the impact of noise interruption is significant when the complexity of the response task is greater, and the potential cognitive arousal due to the workload and potential learning effects may influence response time performances. Finally, a lower extremity cognitive–motor task demonstrates response time behavior similar to such upper extremity cognitive–motor tasks.