Background: Pain management during the administration of local anesthesia is a significant concern in clinical settings. Cryotherapy, the use of extreme cold in medical treatment, has been suggested as a non-pharmacological method for reducing pain during such procedures. This study aimed to evaluate the in-vivo effectiveness of cryotherapy in pain reduction during the administration of local anesthesia. Material and Methods: A randomized controlled trial (RCT) was conducted with 100 participants requiring local anesthesia for minor surgical procedures. The participants were randomly assigned to two groups: the cryotherapy group (n=50), who received localized cooling prior to anesthesia administration, and the control group (n=50), who received no pain-management adjunct. Pain perception was measured using a 10-point Visual Analog Scale (VAS) immediately before and after local anesthesia administration. Additionally, physiological parameters such as heart rate and blood pressure were monitored to assess the stress response. Data were analyzed using independent t-tests and chi-square tests for statistical significance set at p<0.05. Results: The cryotherapy group reported significantly lower VAS scores (mean difference = 2.8, p<0.001) post-anesthesia compared to the control group. Physiological parameters indicated a significantly lower stress response in the cryotherapy group, with decreased heart rate and blood pressure changes during the procedure (p<0.05). Conclusion: Cryotherapy effectively reduced pain and stress response during the local anesthesia administration. This non-pharmacological approach could be considered as part of pain management protocols to improve patient comfort during minor surgical procedures. Further research is recommended to evaluate long-term outcomes and applicability across different patient demographics and procedure types.