Laser-activated irrigation (LAI) of root canal systems depends on the generation of cavitation bubbles in the endodontic irrigant. Physical studies thus far focused on pulse energy, pulse length, frequency, and fiber tip shape, mostly in plain water. This study investigated the effect of endodontically relevant molecules (sodium hypochlorite (NaOCl), 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP), and their combination) in water on physical properties of the resulting solution, and their impact on primary cavitation bubble features. A commercially available 3% NaOCl irrigant was used, as well as an etidronate powder (Dual Rinse HEDP) to be admixed. Physical parameters (density, surface tension, and viscosity) of these solutions were assessed, including HEDP effects in an ascending concentration series of up to 20%. Primary cavitation bubble features (dimensional and temporal) in conjunction with a pulsed erbium-doped yttrium aluminium garnet (Er: YAG) laser equipped with a flat or conical fiber tip were studied in these liquids using a high-speed camera. Solutes increased the solution’s density, surface tension, and viscosity, with an almost linear response to HEDP dosage (Pearson correlation coefficient > 0.95). This reduced the speed of the primary cavitation bubble, and increased its size and lifetime. Increased HEDP concentrations had a pronounced effect on the shape of bubbles generated at the flat tip. NaOCl and HEDP alter the physical properties of water, which, in turn, affect its cavitation behavior.