The efficiency of conventional solid-liquid extraction methods to extract C-Phycocyanin (C-PC) from given biomass is very low because of the resistance offered by the cell membrane for its disruption. The present work aims at developing an efficient protocol for primary extraction of C-PC from dry biomass of Arthrospira platensis. Surfactant (Triton X-100, Tween 20 and Tween 80) and enzyme-assisted (lysozyme) methods were attempted. Process parameters such as incubation time, solid-liquid ratio and surfactant/enzyme concentration were standardized for pre-soaked (120 min) biomass. Enzyme-assisted extraction (at 0.6% enzyme concentration and 16 h incubation) resulted in the highest C-Phycocyanin purity of 1.19 with a satisfactory yield of 82.07 mg/g dry biomass (68.96% extraction efficiency). Among surfactants, Tween 80 (at 0.6% Tween 80 concentration and 50 min incubation) resulted in the highest yield of 71.94 mg/g dry biomass (71.94% extraction efficiency) with a purity of 0.8. Ultrasonication was carried out in combination with these two methods (one at a time) at already standardized conditions to explore the synergy between them. Compared all the methods studied, ultrasonication with enzyme-assisted extraction resulted in the highest C-PC yield of 92.73 mg/g dry biomass (77.92% extraction efficiency) with a purity of 1.09 and was inferred as the best method. •Enzyme-assisted method was used for extraction of C-Phycocyanin.•Surfactant-assisted method was also used.•These methods were applied in combination with Ultrasonication to achieve synergy.•Combining processes increased C-Phycocyanin yield compared to individual methods.•Yield of 82% with 1.09 purity was achieved by Ultrasound-assisted enzymatic method.