The construction of openings next to the columns may be necessary for two-way reinforced concrete slab systems. The ultimate strength of the slab is reduced by these openings, particularly when subjected to cyclic loads. Therefore, the slab is required to be strengthened in such zones. One of the most useful techniques for strengthening the slab-column connection is Carbon Fiber Reinforced polymer (CFRP). Due to its improved mechanical characteristics and high bonding strength, High-Strength Self-Compacted Concrete (HSSCC) has seen an increase in demand over the past few years. Because of these characteristics, it is preferred for use in constructions like multi-story buildings where excellent workability and strength are needed. The main objective of this research is to study experimentally and analytically the seismic behavior of HSSCC slab-column connections with openings strengthened with CFRP. Six full-scale specimens were examined under cyclic loading, including one reference specimen (without openings and without strengthening), while the five strengthened specimens have openings. The most significant factors are the size and location of the openings. Three different opening sizes were tested with a square shape of 200 mm, 228 mm, and 266 mm sides. The openings were at three different locations, next to the column face, at a distance twice the slab thickness (2d) and three times the slab thickness (3d) from the face of the column. The findings indicated that CFRP improved the ultimate load capacity of the strengthened slabs by about (8%–12%) and capacities of the energy dissipation were boosted for all the strengthened specimens. In addition, the opening size did not have a noticeable influence on the specimens’ load-carrying capacity for strengthening specimens. CFRP enhanced the maximum vertical displacement of slabs with openings by about (5%–24%), but for specimens with openings placed at the face of the column, the enhancement was not noticeable. The strengthening has decreased the ductility displacement ratio of all strengthened specimens by about (4%–20%). For additional comparison, the ABAQUS finite element simulation model was created. In comparison to the experimental results, the finite element simulation produced highly agreement results.