In a 2020 interview conducted by the YouTube channel Archipel with the game's creator Shinji Mikami, he talked about the development of Vanquish, which started after he left Capcom and joined PlatinumGames. While he claimed to not remember how he arrived at working on or coming up with the concept for Vanquish, he pitched 5 different project ideas beforehand to Sega and Platinum:

From the start, Mikami wanted to make an open-world game set in a universe similar to the film "Blade Runner", but due to budget, time and staffing constraints, he considered the project to be impossible to make. Regardless, Mikami drafted a design document that he formally pitched to Platinum as a coping mechanism in order to clear his head of the long-gestating idea and work on other projects, stating "I just couldn't switch my mind for a project that fit budget and resources before I gave form to this one. So I just presented it".

Afterwards he moved on to a completely different project; a cel-shaded game set in a universe akin to the works of Studio Ghibli entitled "The Witch and the Piglet". The game was about an evil witch who turned a prince into a piglet and cursed the accompanying village. The villagers would be friendly by day, but at night, they would turn into animals such as horses, pigs, and goats, and do "terrible things" every night, in turn revealing the villagers' evil sides. The main protagonist, a girl with "magical powers who could hover in the sky with an umbrella", had to defeat the witch and break the curse. Mikami believed the game was a mid-scale project that could be easily managed within a given budget and really wanted to make it happen, so he pitched it to Sega. However, Sega strongly declined the pitch, saying that they weren't looking for a game like The Witch and the Piglet.

Angered, Mikami moved on to another project designed exclusively for the Nintendo DS. The game was about a girl with psychic powers and an unknown serial killer who were confined in a hospital. The killer would murder people in the building one by one, and the girl had to figure out if the killer was a doctor, a nurse, or a patient. She used her powers to fight with the killer remotely, move things from a distance, take limited control of peoples' minds, and used a smartphone to send texts and chat during battles, all the while the killer would threaten to kill more people the closer she was to him. One of the central gameplay mechanics involved selecting floating Kanji on the Touchscreen to form two-word phrases such as "Drop Vase" or "Open Door", and watch the results on the hospital's surveillance cameras. Upon pitching it, Sega also rejected the game for the same reason as The Witch and the Piglet, stating the projects were too small and not what they were looking for.

Mikami then recounted an incident during the same meeting, where Sega's executives told him that they were looking for a "Taisaku", or a major project. In response, and angrier than before, he came up with a pitch on the spot called "Keiko and Taisaku", about two delinquent gang leaders, a boy and a girl dressed in high school uniforms, that fought each other, proclaiming "Here, you get Keiko and Taisaku, there's Taisaku in it so it works right?" Sega's executives silently ignored the pitch. Mikami recalled that after this incident came the back-and-forth talks that led to him working on Vanquish.

Sometime in-between these events, Mikami also had an idea for a rhythm action game that he promptly scrapped after pitching it to Platinum, believing that the idea was not as fun as he had thought it was after presenting it.

Near the end of Act 3, Mission 7 "Phantoms", when you go up the lift, you will see enemy robots dancing with an enemy barrier speaker.

According to the game's creative director, Shinji Mikami, the staff hid rhinoceros beetles in the game without him knowing.

There were plans to make a special edition that featured an alternate black suit. However during production the plan fell through.

A lot of the game was inspired by the anime Casshern, with a heavy emphasis on speed for gameplay. The background visuals were initially influenced by the movie Tristan + Isolde, but the staff ended up using a personal style.

There was originally going to be a robot dog companion that assisted in combat and combined with Sam's armor. The concept was eventually dropped.

There is an achievement/trophy called "Fisher is the other Sam" which can be obtained by proceeding on the monorail without being spotted by the enemy troops or searchlights. This is a reference to Sam Fisher in the Splinter Cell series in which stealth was the primary game-play element.