Husillos joins the Hammers following a spell as sporting director at Malaga, where he worked with new West Ham manager Manuel Pellegrini to help the Spanish club to the most successful period in their history.
The 59-year-old has now reunited with his Argentine compatriot at the London Stadium, where he has signed a three-year deal to keep him at the club until 2021.
"I am very excited. West Ham United is a club with huge ambition. The challenge to help deliver that ambition is what really attracted me to the role," Husillos told the club's official website.
"I know the manager well and know he wants to deliver an exciting brand of attacking football. It will be my job to supply him with the tools to do just that. I am very much looking forward to working with Manuel Pellegrini again. We had great success together at Malaga, reaching the Champions League, and he is someone that I have huge respect for.
"I have seen West Ham play many times before. The fans are very passionate and close to the team, and I hope we can give them a team to be proud of next season."
Co-chairman David Sullivan added: "He has worked in six or seven different countries and it's that global experience we hope will serve us well as we scout the world to bring West Ham United some exciting new talent.
"He is also highly experienced at helping young players fulfil their potential and we believe we have an exciting crop of emerging players here. Mario will take complete, strategic control of all player recruitment and, alongside Manuel, has the full support and confidence of myself and David Gold to lead that department.
"On behalf of everyone at West Ham United, I would like to welcome Mario Husillos and his family to the club."
Pellegrini also told the club's website: "It was very important to me that we appointed the right person to lead our player recruitment process and I know from working with him that Mario will be a great asset for us.
"Mario has great experience and a fantastic knowledge of players. We have already had positive discussions about his role and the areas of the squad that we want to improve, and I am sure he will become a key figure for the club. His worldwide contacts will help attract talent to play at London Stadium."