Background The most common cause of pain after cardiac surgery is median sternotomy. Poor postoperative (PO) pain control has serious effect on pulmonary and cardiovascular systems and induces stress and hyperglycemia. Good PO analgesia helps early recovery and discharge. Aim The primary aim was to compare analgesic efficacy of continuous presternal bupivacaine infusion and ultrasound-guided bilateral pectoral nerve 2 block (Pec 2). The secondary aim was to evaluate their efficacy in controlling respiratory parameters, duration of PO ventilation, ICU stay, and hospital stay. Patients and methods A total of 100 patients of American Society of Anesthesiologists status II were randomly divided into group I, which received continuous presternal bupivacaine infusion, and group II, which received ultrasound bilateral Pec 2 block. PO visual analog scale (VAS) was recorded at extubation, 3, 6, 12, 18, and 24 h. Pain severity was divided into four grades: no pain, VAS less than 4; mild, VAS 4–5; moderate, VAS 6–7; and severe, VAS greater than 7. Morphine, bupivacaine consumption (mg), and number of request of analgesia in first PO 24 h and inspiratory flow rate (IFR) (l/min) at extubation, 3, 6, 12, 18, and 24 h were recorded. Arterial blood gas parameters were recorded at extubation, 3, 6, 12, and 24 h. Duration of PO ventilation (min), ICU stay (h), and hospital stay (days) were recorded. Results PO VAS, pain severity, IFR, and arterial oxygen tension/inspired oxygen fraction (PaO2/FIO2) were significantly higher in group II at all study times. Morphine, bupivacaine consumption, and number of request of analgesia in first PO 24 h were significantly higher in group I. Duration of PO ventilation, ICU stay, and hospital stay were significantly longer in group I. Conclusion First, Pec 2 block was safe and effective in controlling sternotomy pain with lower VAS and pain severity, less bupivacaine, morphine consumption, and less request of PO analgesia. Second, Pec 2 block showed better IFR and PaO2/FIO2, with shorter duration of PO ventilation, ICU stay, and hospital stay.