Cyclic adenosine monophosphate (cAMP) plays a central role in sperm physiology. Various cAMP up-regulators, both cAMP analogs and phosphodiesterase (PDE) inhibitors, have been used in handling human sperm in vitro, though conflicting results and variable responses among patients have been reported. This study aims to evaluate the ability of two compounds - Sp-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole 3'-5'-cyclic monophosphothioate (cBiMPs), a cAMP analog, and TAK-063, a specific PDE10A inhibitor - to enhance human sperm motility parameters and, consequently, improve sperm preparation procedures. Our results showed that both cBiMPs and TAK-063 significantly enhanced human sperm motility and hyperactivation compared to the control (dimethyl sulphoxide (DMSO)). They also increased protein phosphorylation levels without inducing premature acrosomal exocytosis or DNA fragmentation. The enhancement of sperm motility persisted for 4 h after their removal, surpassing the effects of known cAMP analogs (8-bromo-adenosine-3', 5'-cAMP (8-Br-cAMP) or dibutyryl cAMP (db-cAMP)) or PDE inhibitors (3-isobutyl-1-methylxanthine (IBMX) or pentoxifylline (PTX)). Furthermore, the presence of cBiMPs or TAK-063 during sperm selection resulted in higher recovery rates in comparison to the control, and these compounds effectively improved sperm motion in both fresh and cryopreserved samples with impaired motility. In conclusion, cBiMPs and TAK-063 exhibit potent and sustained effects on human sperm motility, enhancing the efficiency of sperm preparation techniques. The ability to improve sperm motility holds significant implications for male infertility treatment, facilitating the use of low complexity techniques such as intrauterine insemination or in vitro fertilization, and may also aid in selecting viable testicular sperm for intracytoplasmic sperm injection.