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Background and Aims Minimally invasive approaches in cardiac surgery offer several advantages, including reduced surgical trauma, faster recovery, and lower risk of complications. However, they are linked to a higher risk of intercostal nerve injury, which can cause more intense postoperative pain. This pilot prospective study compared three strategies for managing pain after mini-thoracotomy: (1) intercostal nerve cryoablation, (2) regional fascial blocks—Erector Spinae Plane Block (ESPB) and Pectoralis II Block (PECS II), and (3) standard pharmacological analgesia without regional techniques.Methods The pilot study included ten patients aged 48 to 65 years (median 48) who underwent mini-thoracotomy for minimally invasive cardiac surgery. It was approved by the hospital ethics committee and registered at clinicaltrials.gov ( NCT03915301). Group A (n = 3) received perioperative intercostal nerve cryoablation. Group B (n = 45) received regional fascial blocks (ESPB + PECS II) before thoracic closure. Group C (n = 30) received standard analgesic treatment. Pain was assessed using the Numerical Rating Scale (NRS), and daily analgesic use was recorded for five postoperative days.Results Group A (cryoablation) reported the lowest pain intensity (NRS 0–1 during the first 12 hours postoperatively) and minimal use of both opioid and non-opioid analgesics. Group B (ESPB + PECS II) showed moderately higher NRS scores and greater analgesic use compared to Group A, but better outcomes than the control group. Group C had the highest pain intensity and overall analgesic requirements, including repeated bolus doses and regional blocks.Conclusions Intercostal nerve cryoablation appears to be an effective and safe method for controlling acute postoperative pain after mini-thoracotomy, significantly reducing analgesic use compared to other techniques. ESPB and PECS II are common regional anesthesia methods in thoracic procedures, including mastectomies and chest wall surgeries, and showed moderate effectiveness in this study. These findings support further research into cryoanalgesia as part of multimodal pain management after thoracotomy.