Objective: This study assessed the efficacy of erbium, chromium: yttrium-scandium-gallium-garnet (Er,Cr: YSGG) laser-activated irrigation (LAI) of ethylene diaminetetraacetic acid (EDTA) and phytic acid on the removal of calcium hydroxide (CH) and triple antibiotic paste (TAP) from root canals. Background data: Although some studies investigated the efficacy of LAI of EDTA irrigation, no study has been conducted to investigate the efficacy of LAI of phytic acid in the removal of CH and TAP from root dentin. Materials and methods: Root canals of extracted maxillary incisors (n = 80) were instrumented using rotary files and thereafter were split longitudinally. Following preparation of a standardized groove in the apical region of one root half, the roots were randomly divided into two groups according to the intracanal medicaments placed into the grooves: (1) CH and (2) TAP. The roots were reassembled, and the specimens were further assigned into four groups (n = 10/group) defined by the final irrigation solution (EDTA and phytic acid) and irrigation technique (needle irrigation and LAI) used for removal of the medicaments. The data were analyzed statistically using Kruskal-Wallis and Mann-Whitney U tests. Results: For both EDTA and phytic acid, LAI was more efficient than needle irrigation in removing both CH and TAP (p < 0.05), but none of the tested techniques completely removed CH. Irrespective of the tested irrigation solutions and techniques, significantly less TAP remained in canals (p = 0.0001), with TAP being completely removed by LAI. Irrigation with phytic acid showed better removal efficacy than EDTA in the absence of statistical significance. Conclusions: Er, Cr: YSGG LAI of EDTA and phytic acid completely removed TAP and effectively reduced CH on root dentin.