This study tested the hypothesis that pectoralis II (PECS II) + serratus plane blocks would reduce opioid consumption and improve outcomes compared with standard practice in minimally invasive cardiac surgery. A retrospective and observational study was realized in the intensive care unit (ICU) setting of “ICLAS GVM, Istitituto Clinico Ligure Alta Specialità, (Rapallo, Italy)”, including adult patients who underwent right minithoracotomy for replacement/plastic aortic, mitral and tricuspid valve or atrial myxoma resection in cardiac surgery. Seventy-eight patients were extracted by the database and divided into two groups. Group 1 (41 patients) received ultrasound-guided PECS II + serratus plane blocks with Ropivacaine 0.25% 10 mL + 20 mL + 30 mL. Group 2 (37 patients) received intravenous opioids analgesia with morphine 20–25 mg/day or tramadol 200–300 mg/day. The primary outcomes were: the pain perceived: Critical-Care Pain Observation Tool (CPOT) score; the opioids consumption: mg morphine or tramadol, or µg sufentanyl administered; and mg paracetamol, toradol, tramadol or morphine administered as a rescue. The secondary outcomes were the hours of orotracheal intubation and of stay in ICU, and the number of episodes of nausea, vomiting, delayed awakening and respiratory depression. Group 1 vs. Group 2 consumed less opioids (Sufentanyl p < 0.0001; Morphine p < 0.0001), had a lower pain perceived (p = 0.002 at 6 h, p = 0.0088 at 12 h, p < 0.0001 at 24 h), need for rescue analgesia (p = 0.0005), episodes of nausea and vomiting (p = 0.0237) and intubation time and ICU stay (p = 0.0147 time of IOT, p < 0.0001 stay in ICU). Ultrasound-guided PECS II + serratus plane blocks demonstrated better than intravenous opioids analgesia in patients undergoing minimally invasive cardiac surgery.